Introduction_to_cardiac_physiology_electrophysiology [TUSOM | pharmawiki] (2023)

learning goals

At the end of the self-study you should be able to:

  1. Describe the sequence of events that produce the heart's normal pattern of firing and contracting (normal sinus rhythm).

  2. Describe the main components (waves and intervals) of the surface electrocardiogram (lead I) and how they correspond to the propagation of conduction and repolarization in different regions of the heart.

  3. Explain the role of gap junctions in mediating cardiac conduction and how their function is altered by changes in intracellular pH and [Ca].

  4. Explain which ion currents modulate the 5 different phases of the ventricular action potential.

  5. Explain which ionic currents are primarily responsible for mediating the rise (& conduction) of action potentials in the atrium, ventricle, and AV node.

  6. Explain the role of the AV node in regulating ventricular rate in the presence of an atrial tachyarrhythmia.

  7. Explain which ionic currents modulate the automatics in the SA node and in the Purkinje fiber system.

  8. Explain how changes in extracellular K ion concentration alter resting potential, conduction velocity, and automatism.

  9. Explain the mechanisms by which autonomic neurotransmitters modulate conduction in the AV node and automatism by changing IF, ICASHand meCa.

  10. Explain the fundamental events linking excitation and contraction in cardiac muscle and how contractility can be modulated by factors affecting intracellular Na and Ca concentration.


  • APD:Duration of the action potential. The duration of the action potential, typically measured at 50% or 90% of complete repolarization, relative to the peak amplitude of the action potential.

  • Inventory management:Effective Refractory Period. The period of time after an action potential rise (or QRS complex in vivo) during which the heart resists stimulation by a physiological stimulus. During this time, the heart is unable to generate a second conducted action potential when stimulated. (The typical definition of a “physiological stimulus” is an electrical shock delivered at twice the electrical threshold for producing a conducted beat after a long diastolic interval).

  • Cardiac output (CO):The volume of blood pumped by the heart in one minute (normal is ~5 l/min)

  • Stroke Volume (SV):the volume of blood ejected from the left ventricle during one contraction (normal = 70 ml)

  • Ejection fraction (EF):the proportion of blood volume in the left ventricle that is ejected in one beat (normal = 60%)

  • Sino-atrial node (SAN or SA node):the specialized tissue region in the upper right atrium (Figure 1) that is specialized for automatics. This region has the highest level of automaticity in the normal heart. It sets the pace at which the heart beats under physiological conditions. Two other regions in the normal heart (the AV node and Purkinje fibers) have a lower degree of automation and can serve as backup pacemakers in the event of damage to the SA node or blockage in the conduction of action potentials from the SA node.

  • Atrioventricular node (AVN or AV node):the specialized region of tissue between the atria and ventricles that is specialized for slow conduction and behaves like an electrical filter at high atrial rates (e.g., atrial fibrillation). The L-type Ca current is primarily responsible for mediating conduction in this region of the heart.

  • Bundle of His & Bundle Branches:The bundle of His extends from the distal end of the AV node and divides into smaller bundle branches in the left and right ventricles, terminating in Purkinje fibers. Specialized in the rapid conduction of the cardiac action potential.

  • Purkinje fibers:A "spider web-like" network of specialized, elongated heart cells that spread across the inner surface of the ventricles (endocardium). They contract only weakly and are specialized in the rapid transmission of action potentials to the ventricular muscle.

  • Ion current:The cardiac action potential is generated by the interaction of many different ionic currents. Most are selective for either Na, K, Ca, or a mixture of Na & K. Each stream has its own "historical" name (or names) and is caused by the time-dependent opening of voltage-gated channels. Most channels have recently been renamed after the genes that have been cloned and identified as the source of each stream. Currents are abbreviated with the letter “I” (as in Ohm's law: ΔV = IR). For example meAlreadyis the designation for a sodium current.

The definition

  • Automatism:the ability to spontaneously depolarize and generate an action potential.

  • Management:Movement of a cardiac action potential from one part of the heart to another.

  • contractility:the potential to do work, often measured as the ability of muscle tissue to develop tension or shorten. Affected by heart rate, catecholamines and other factors.

  • Effective Refractory Period (ERP):the period of time after an action potential rise during which a second subsequent action potential cannot be generated by a physiological stimulus.

  • cardiac arrhythmia:an abnormality in the rate, rhythm, or pattern in which the heart contracts.

Illustration 1.Sketch of the cardiac conduction system (without heart muscle). The sinus node (SA) is the normal site of origin of the electrical impulse (action potential) that causes the heart muscle to contract. The SA node is located at the top of the right atrium. The atrioventricular (AV) node specializes in conducting slowly and acting like an electrical filter to prevent the ventricles from being paced faster than they can fill with blood when an atrial tachyarrhythmia occurs. The bundle of His and bundle branches are specialized for fast conduction and deliver the wavefront of action potentials to the inner ventricular myocardium (endocardium) via a mesh-like network of Purkinje fibers. Reproduced byWikipedia Commons.

Basic Anatomy: The heart is a four-chambered pump

The primary function of the heart is to move sufficient blood from the venous system to the arterial side of the circulatory system under sufficient pressure to sustain the body's circulatory needs. As shown in Figure 2, the heart consists of four chambers that act as two separate pumping systems. The right atrium and right ventricle (the right heart) pump deoxygenated blood collected from the large veins (superior and inferior vena cava) to the pulmonary circulation via the pulmonary artery. The left atrium and left ventricle (the left heart) pump oxygenated blood from the pulmonary system to the systemic circulation. The atria, which sit dorsal to the ventricles, are relatively thin-walled and their primary function is to serve as a blood reservoir and to help fill the ventricles with blood. In this sense, they serve as “primer pumps”. The ventricular chambers have much thicker walls (the left one is thicker than the right one). They can be thought of as the heart's "power pumps" as they provide the primary force for pumping blood to the pulmonary and body circulation systems. The pattern in which the heart contracts and relaxes is cyclic and transitions into a relaxation phase (Diastole) and a contraction period (Systole).

Figure 2.Basic anatomical features of the heart and patterns of blood movement. When the heart relaxes during diastole, blood flows passively into the atria and through them into the ventricles. The contraction of the atria at the end of diastole helps fill the ventricles. This "atrial kick" contributes ~10% to cardiac output. As the ventricles contract at the beginning of systole, the increase in pressure causes the tricuspid and mitral valves between the ventricles and the atria to close (associated with the first heart sound, S1). The further increase in pressure that occurs after the tricuspid and mitral valves close causes the pulmonary and aortic valves to open, allowing blood to be ejected into the pulmonary and systemic circulations. Approximately 70 mL (~60% of the blood in the ventricles at the end of diastole) is ejected into the circulation during systole. This includes the normal "Ejection fraction” (EF). Changed byWikipedia Commons.

The normal sinus rhythm

The coordinated and synchronized contraction of muscle cells in each heart chamber, which occurs during each cardiac cycle of systole and diastole, is accomplished by a regular pattern of excitation that precedes each contraction. The time intervals at which the cardiac impulse reaches each region of the heart during each beat of the cardiac cycle are shown in Figure 3.

The normal pattern of arousal begins with the spontaneous occurrence of action potentials in theSinusknoten (SAN), which spontaneously generates action potentials with a frequency of 60-100 per minute. These action potentials propagate rapidly through the left and right atria and into the superior region of the atriumatrioventricular node (AVN). Routing through the AVN is slow, requiring more than a hundred milliseconds. This delay allows time for the atria to contract and helps the ventricles fill with blood before they are stimulated to contract.

Once the impulse leaves the distal end of the AVN, it enters thebunch of his, which then divides intoleft and right bundle brancheswhich lie beneath the endocardial surface on either side of the ventricular septum. Each bundle branch spreads downward from the base of the ventricle to the apex. These branches continuously divide into smaller onesPurkinje fiberswhich spread and cover all parts of the ventricular endocardium. Conduction through the His-Purkinje system is very rapid, resulting in a"almost" simultaneous stimulation of all muscle cells in both chambers. As a result, they contract at almost the same time. This coordinated contraction produces a reduction in ventricular volume, expelling blood through the valves into the pulmonary and systemic circulation.

Figure 3.The transmission pattern of cardiac impulses through the heart during normal sinus rhythm. Reproduced from theWikipedia Commons.

Cardiac muscle cells are connected to each other as a syncytium

In contrast to skeletal muscle, cardiac muscle fibers are made up of many individual muscle cells connected in series by one or more “intermediate discs” (Figure 4). At the molecular level, intercalated discs consist of a set of gap junctions that provide low-impedance electrical coupling between myocardial cells (atrial or ventricular). This design allows the electrical currents generated by an action potential in one cell to excite (depolarize) neighboring cells to threshold, so that the excitation wavefront propagates through the heart muscle (atrial or ventricular) in the direction in which the muscle fibers are aligned. Such cell-to-cell communication is necessary to produce a coordinated contraction of muscle cells within each heart chamber.

Gap junctions also allow for the propagation of metabolic or second messenger signals between cells. Gap junctions can "close" under pathologic conditions that commonly occur during myocardial ischemia (eg, chronic depolarization of adjacent cells, low pH).I, high approxI). Increasing gap junctional resistance may slow conduction, but may also help protect healthy myocardium from damage from a neighboring region of myocardial ischemia by physically isolating healthy cells from ischemic cells with pathologically low pHI, high approxIand depolarized resting potentials (analogous to closing the watertight doors to isolate the damaged area of ​​a torpedo-hit ship).

Figure 4.Schematic of a cross section of the ventricular myocardium. Cardiac muscle cells are striated in appearance and roughly rectangular in shape. Myocardial cells are serially connected to one another by one or more intercalated discs composed of a very high density of low-resistance gap junctions made up of connexin proteins that combine with connexin proteins on neighboring cells. These low-impedance connections allow action potentials to be passed from one cell to another.

The surface electrocardiogram

The propagation of depolarization and repolarization that occurs during each heartbeat produces voltage changes that can be measured with electrodes placed on the body's surface. When measuring the voltage changes along the frontal plane between the right and left arms (lead I), a voltage profile similar to that in Figures 3 and 5 is observed. The initial propagation of the depolarization across the right and left atria creates a voltage deflection known asP wave.

The delay in conduction that occurs in the AV node creates a prolonged isoelectric pause after the P wave, which accounts for much of the P wavePR Interval(Figure 5). Changes in conduction time through the AV node, which may result from changes in autonomic tone, drug effects, or cardiac disease, result in changes in the PR interval.

The depolarization of the ventricular myocardium is detected asQRS complex, where the initial downward excursion (Q-wave) reflects the initial depolarization of the septum before the depolarization of the rest of the right and left ventricles. The depolarization propagates from the endocardium (where the Purkinje fibers terminate) outward to the epicardium. Factors affecting the normal propagation of depolarization in the ventricular myocardium (sodium channel blockers, myocardial ischemia, hyperkalemia) prolong the QRS duration.

TheT-Wellereflects ventricular repolarization, andthe QT interval reflects the time for complete ventricular repolarization. While the QT interval also includes the QRS interval (the time for ventricular depolarization), clinically there are times when the QRS takes on an odd shape and merges with the T wave, making it impossible to detect the end of the QRS to distinguish from the beginning of the QRS T wave. Therefore, the QT interval is used as a convention to measure the time it takes for the ventricle to repolarize after the onset of depolarization.Events abnormally prolonging the QT interval(K-channel blockers, mutations in ion channels - long QT syndrome)are typically proarrhythmic (increasing the likelihood of multifocal ventricular arrhythmias such asTorsade de Pointes) and are therefore potentially life-threatening.

Because the duration of action potentials is shorter in the epicardium than in the endocardium, repolarization occurs first in the epicardium, followed by repolarization in the endocardium (Figure 5). This causes the T wave to have an upright configuration. The surface electrocardiogram can be measured from many different orientations (e.g., the standard clinical electrocardiogram is measured using 12 surface leads), which can be used to accurately determine the nature and extent of various types of cardiac pathologies. More details are provided in separate modules.

Figure 5.Schematic representation of the heart, the electrocardiogram (ECG) and action potentials recorded from different regions of the heart. The sinus node (SAN), the atrioventricular node (AVN) and the Purkinje fibers show automatism (phase 4 depolarization). Action potentials in the SAN and AVN have a slow upstroke velocity generated by the L-type Ca current. The upstroke in cells outside the nodes is generated by the Na current. The duration of the atrial action potential is approximately one-third the duration of the ventricular action potential. Epicardial action potentials have a shorter duration and a more pronounced phase 1 notch compared to endocardial action potentials. These differences in action potential configuration result from regional differences in ion channel expression. The different components of the surface ECG reflect different events in the cardiac cycle (as indicated by the color coding). The P wave reflects the time course of the propagation of the atrial depolarization. Conduction through the AVN occurs during the isoelectric portion of the PR interval. The QRS duration indicates the time for ventricular depolarization, and the QT interval is used as a measure of the time for ventricular repolarization (Adapted from Harvey & Grant, 2018).

There are clear regional differences in the impact potential properties

Cardiac action potentials are complex in shape, distinctly different, and of much longer duration compared to those recorded from nerves or skeletal muscle.

Conventionally, the cardiac action potential is divided into5 different phases (0 to 4)(see Figure 5). The phases are labeled:

  • Phase 0 (upstroke action potential)

  • Phase 1 (Notch or rapid repolarization phase)

  • Phase 2 (Plateauphase)

  • Phase 3 (rapid repolarization period)

  • Phase 4 (diastolic Period)

These different phases of the action potential result from the opening and closing of different voltage-sensitive channels that selectively conduct different ions. As shown in Figure 5, the shape of the cardiac action potential is quite different when recorded from different regions of the heart. This follows from the fact thatCells in different regions express different densities of the different ion channels that regulate the shape of the cardiac action potential. Because of these differences in ion channel expression, cells from other regions differ from ventricular myocytes by not having a clear plateau phase (e.g., SA node) or by having a small or absent phase 1 component (e.g., SA node). , ventricular endocardium) exhibit automatism (SA node, AV node, Purkinje fibers) or have a slow Ca-mediated upstroke (SA and AV node) (Figure 5). Differences in ion channel expression also cause the duration of the action potential in atrial cells to be much shorter (~1/3 the duration) than for action potentials in the ventricular myocardium or Purkinje fibers.

Several ionic currents underlie the 5 phases of the cardiac action potential

The cardiac action potential gets its special form from the opening and closing of various voltage-sensitive channels. The flow of ions through each channel drives the membrane potential toward the equilibrium potential for that ionic species. For example, when heart cells remain unstimulated (phase 4), the only type of channel that opens regularly is an "inward rectifying" K-selective channel that produces a K-current called IK1(the first discovered cardiac K-current).

The selective permeability of the resting membrane for K ions causes the potential difference across the resting cell membrane to approach the equilibrium potential for K ions (EK≈ -95) (Figure 6). In contrast, when cardiac cells are partially depolarized by an invading action potential, these K channels close and a large number of excitable Na channels open transiently. This drives the membrane potential towards the equilibrium potential for Na ions (EAlready≈ +60) and generates the upstroke action potential (phase 0). Almost all Na channels are rapidly inactivated within ~1 ms at normal body temperature. However, a small (~1%) fraction of Na channels are not completely inactivated and contribute to the maintenance of the plateau phase of the ventricular action potential. This non-inactivating component can be blocked by Na channel blockers (e.g. lidocaine).

Other voltage and time dependent inflow and outflow currents are then activated in a time dependent sequence after phase 0. One of the first activated currents is the transient outflow (ITo), which produces a phase of rapid repolarization (phase 1). (The charge carrier for ITois K). The repolarizing effect of ITois balanced by activation of the L-type Ca current, resulting in a plateau phase (phase 2) of several hundred milliseconds, during which the voltage changes little over time. Ca influx is an important “trigger” for excitation–contraction coupling (discussed later). A slow inactivation of the Ca current coupled with an activation of additional outward K currents (IKr& IKs) eventually leads to a phase of rapid repolarization (phase 3). The behavior of many of these ion channels can be modulated by the presence of neurotransmitters, drugs, and changes in metabolic conditions.

Figure 6.Ionic basis for the resting and action potential in a ventricular heart cell. The action potential is divided into phases 0 through 4. Each phase results from a change in the balance of the inward and outward ionic currents that are activated upon membrane depolarization. The primary currents underlying each phase are: Phase 0: Na current (IAlready); Phase 1: transient outward K-current (ITo); Phase 2: L-type Ca current (ICa); Phase 3: delayed rectifier K-currents (IKr& IKs); Phase 4: inward rectifying K-current (IK1). The change in dominant conductance during each phase produces either a net depolarization or hyperpolarization and gives the action potential its characteristic shape.

The channel that produces meK1is often referred to as an "inward rectifier". Inward rectification describes the channel's behavior of conducting current most readily in the inward direction rather than the outward direction (Fig. 7), similar to an electrical diode. Inward rectification can be caused by substances in the cytoplasm (e.g. Mg2+I) or associated with the inner surface of the cell membrane (spermine, spermidein, etc.) which are swept into the channel (like driftwood with the tide) when the direction of flow is strongly outward - i.e. whenever the voltage with respect to E becomes positiveK. This allows a channel with an otherwise low voltage dependency to "switch off" at voltages positive to E.K. The biological advantage of reducing the amplitude of this current at voltages positive to EKis that it allows other currents to determine the shape of the cardiac action potential without having to "dominate" an otherwise massively large outward current, and saves the energy (ATP) that would be required to pump all the K ions, that would otherwise be lost back into the cell. A longer action potential duration with a plateau phase is also important for excitation-contraction coupling regulated by calcium influx during phase 2.

Figure 7.Internal Correction Mechanism. If the voltage at the cell membrane is positive for EKThere is a driving force for K ions to exit the cell and create an outward current. However, when K ions leave the cell, Mg2+Ions and/or other impermeable substances in the cytoplasm are swept into the channel opening and block ion outflow from the cell (above left). This phenomenon creates a sharp curvature in the current-voltage relationship (right image) that would otherwise be linear and obey Ohm's law: IK = ΔV/R (where ΔV = VM– EK). The linear slope predicted for a "non-rectifying" IV relationship is indicated by the dashed line and reflects a constant voltage-independent channel conductance. Without rectification (dashed line), at positive voltages a huge outward K-current would be generated, producing a very short APD, and this would leave no time for the Ca influx required for coupling between excitation and contraction of the heart muscle .

The resting potential is a function of the extracellular K concentration

As mentioned above, at rest, healthy heart muscle cells have cell membranes that areselectively permeable to K ions, and therefore have resting potentials close to the equilibrium potential for K ions (EK≈ -95 if [K]Ö= 4mM) (Figure 6). Therefore, the resting potential can be predicted by the difference in extracellular and intracellular K concentrations according to the Nernst equation (Figure 8). Hyperkalemia (K)Ö> 5 mM) leads to a depolarization of the resting potential. Systemic hyperkalemia can result from abnormalities such as Addison's disease (destruction of the adrenal glands—no aldosterone production), renal failure, or treatment with K-sparing diuretics. In addition, myocardial ischemia produces local tissue hyperkalemia, which can reach levels of 10–20 mM within minutes after occlusion of a coronary artery (Figure 8). Consequently, a common event during myocardial ischemia is a depolarization of the resting potential. This will be covered in more detail in an upcoming module on cardiac arrhythmias.

Figure 8.The relationship between the extracellular potassium concentration ([K]Ö) and resting potential (RP) in a ventricular muscle cell. The membrane's selective permeability to K results in a resting potential (RP) that is close to the Nernst potential for K ions (EK) if [K]Öis greater than ~3mM. At lower K concentrations, the relationship deviates from the Nernst relationship due to limited permeability to other ions. Note that hyperkalemia (high [K]Öleads to membrane depolarization. The resting potential becomes zero when both internal and external [K] are equal.

Na channel gating regulates both conduction and refractoryity in the myocardium

Within a millisecond of the Na channels opening during phase 0, they enter an inactivated closed state due to the rapid movement of an inactivation gate, which disrupts the flow of Na ions through the channel. As shown in Figure 9, Na channels remain in this inactivated and non-excitable state throughout the action potential plateau until late in phase 3, when the membrane potential becomes sufficiently negative to cause a majority of the Na channels to switch to their quiescent (excitable ) conformation returns. Because of this voltage-dependent behavior, cardiac tissue cannot generate a second conducted action potential until, at the end of phase 3, a sufficient number of Na channels have regained their excitability (by returning from the inactivated to the quiescent state). This is an important feature of heart tissue by preventing the heart from rapidly rebounding, which would prevent the ventricles from filling with blood. This behavior is reflected in measurements of theEffective Refractory Period (ERP)AndRelative Refractory Period (EIA).

The ERP.The ERP is defined as the length of time during which cardiac cells remain inexcitable to a physiological stimulus after an action potential rise. It can be assessed clinically by placing a pacing and recording catheter on the inner wall of the heart (typically via a venous access route) and stimulating the heart with two stimuli (S1 and S2) at different S1-S2 intervals. As the S1-S2 interval is gradually shortened, the first S1-S2 interval that does not produce a second conducted beat (QRS complex) defines the ERP.

The RRP.The relative refractory period is the time interval after ERP during which conduction occurs, but at a rate less than maximum. This phenomenon results from the fact that not all Na channels have recovered from inactivation during this period of time. The point in time when virtually all Na channels have recovered from inactivation and the conduction rate is maximal marks the end of RRP. Beats generated during the RRP have a slower rate of upward movement and create a wider QRS complex on the ECG.

Figure 9.Changes in Na channel state during a typical action potential. At the end of diastole, all Na channels are at rest (R). During phase 0, Na channels go to an open state (O) for ~1 ms and then to an inactivated state (I). Approximately 99% of the Na channels remain in an inactivated (closed and non-conducting) state until the end of phase 3, when the membrane potential becomes negative enough to return the majority of the Na channels to the quiescent (excitable) state. The time course with which the Na channel returns from the inactivated to the quiescent state determines ERP and RRP.

Steady-state Na channel inactivation

A second important implication of the voltage-dependent gating of Na channels is that the proportion of Na channels that are free of inactivation at the onset of an action potential rise depends on the resting potential (see Figure 10). Cells with a depolarized resting potential (positive to -80 mV) have reduced Na current amplitude and conduct action potentials more slowly than normal due to Na channel inactivation. When the Na current is sufficiently reduced,complete blockthe line occurs.Depolarized resting potentials are a common feature of cardiac cells subjected to severe strain, hyperkalemia, or ischemia. Excessive stretching of myocardial tissue can activate stretch-activated channels that are nonselective for different ions, and therefore the resting membrane potential of EK, and more towards 0 mV. Chronic depolarization of the RP, resulting in a reduction in Na current amplitude, decreases conduction velocity (i.e., widens the QRS) and can cause cardiac arrhythmia. This topic is covered in other modules.

Figure 10.Dependence of the Na current amplitude on the resting potential (Na current availability curve). At normal or hyperpolarized resting potentials, the majority of Na channels are in a quiescent state and can be opened by a sudden depolarizing stimulus (i.e., invading action potential). As a result, a maximum Na current can be evoked during conduction of the action potential. As the resting potential becomes more depolarized, a progressively larger fraction of the channels enter an unexcitable inactivated state and cannot be reopened by a depolarizing stimulus. This results in a reduction in available Na current and slower conduction. Cells exposed to pathological conditions often have depolarized resting potentials, resulting in Na channel inactivation and conduction block.

Neural control of the heart

The rate and force at which the heart contracts is modulated by both the sympathetic and parasympathetic branches of the autonomic nervous system (Figure 11). The level of basal tone (neural stimulation) at the heart is predominantly vagal (as opposed to sympathetic) when the body is at rest. In normal adults, the average resting heart rate is about 70 beats/minute at rest, but can increase to well over 100 during physical exertion or emotional arousal (fight or flight responses) and decrease by 10 to 20 beats/minute during sleep. Sympathetic nerves innervate both the atria and ventricles (including both the SA node and AV node), while the vagus nerves innervate only the atria, SA node, AV node, and Purkinje fiber system.

Sympathetic nerve stimulation increases heart rate, AV node conduction velocity, and the force of ventricular contraction. In contrast, stimulation of vagus nerves decreases heart rate and conduction velocity through the AV node, but has little effect on ventricular contractility.

The distribution of the sympathetic and parasympathetic nerves to the heart is asymmetric, and as a result, stimulation of the right vs. left branch can elicit different responses (see Figure 11). For example, stimulation of the right vagus nerve results in a greater deceleration in sinus rate, while stimulation of the left vagus nerve results in a greater deceleration in AV nodal conduction. Clinically this is of little importance since both the right and left vagus nerves are stimulated simultaneously, but experimentally (e.g. in animal studies) one can isolate and selectively stimulate the right vs. left vagus nerves, which lie adjacent to the carotid artery in the neck area.

Figure 11.Anatomical distribution of autonomic nerves that regulate cardiac function. Sympathetic fibers from the left and right sides of the spine innervate both the atrium and ventricles. The sympathetic fibers from the right and left sides of the body are distributed asymmetrically to the various structures in the heart. Stimulating the sympathetic nerve on the right side results in greater increases in heart rate compared to stimulating the sympathetic nerve from the left side. In contrast, stimulation of the left sympathetic nerve produces a greater increase in ventricular contraction. Vagus fibers are also asymmetrically distributed. Right vagus nerve stimulation mainly affects the SA node (reducing its firing rate), and left vagus stimulation mainly affects the AV node (reducing AVN conduction velocity and increasing AVN-ERP).

signal transduction mechanisms

The cellular mechanisms responsible for mediating the actions of the parasympathetic (vagal) and sympathetic nerves on cardiac function are shown in Figure 12.

Figure 12.Signal transduction systems for muscarinic and beta-adrenergic receptor-effector coupling in cardiac tissue.Norepinephrine(Norepi) binds to beta1-adrenergic receptors coupled to adenylate cyclase (AC) via G protein GS. Activation of adenylate cyclase by GSincreases the synthesis of the second messenger cAMP, which activates protein kinase A (PKA). PKA phosphorylates a variety of proteins, including the L-type Ca channel. Phosphorylation of the L-type Ca channel increases Ca influx, resulting in an increase in both heart rate and contractility.Acetylcholine(ACh) binds to type 2 muscarinic receptors, which activate the “inhibitory” G protein G when stimulatedI. Activation of GIinhibits adenylate cyclase and activates a K channel (resulting in K efflux). Both of these effects decrease pacing, shorten APD, and counteract the effects of norepinephrine mediated by the production of cAMP.

Modulation of AVN conduction and ERP by the nervous system

Cells in the SAN and AVN behave slightly differently than atrial or ventricular cells. As previously shown in Figure 5, cells in the nodal regions have a less negative diastolic membrane potential (these cells never really "rest" in an electrical sense) and they have a much slower upward movement rate during Phase 0. The less negative resting potential is due to lower K+ permeability in these cells (small IK1), and the slower upstroke speed is due to conduction being primarily doneCa current mediated.

TheThe Ca current is 100-1000 times smaller than the Na current, making it a weaker depolarizing stimulus. A weak current produces a slower depolarization rate of neighboring cells and a slower conduction speed. Because the Ca current is so small, the upstroke is caused by an action potentialThe Ca influx can be physiologically antagonized by K currents that are of a similar magnitude, but flow in the opposite direction. For this reason, both conduction velocity and ERP in the AVN are modulated by events affecting the relative balance of both Ca and K currents. As shown in Figure 13, sympathetic tone produces an increase in AVN upstroke velocity and conduction velocity and a decrease in AVN ERP. These effects are due to a sympathetically induced increase in the amplitude of the L-type Ca current through stimulation of beta-adrenergic (β1) receptors (Figure 13). Other beta-adrenergic agonists such as epinephrine (which is released from the adrenal gland during fight or flight responses) have similar effects.

Vagal stimulation produces the opposite effects. Vagal stimulation releases acetylcholine, which in turn activates a potassium current (ICASH) after stimulation of muscarinic receptors (m2) (Fig. 12). Muscarinic stimulation can also partially reduce the amplitude of the L-type Ca current (eg, by 25%) by inhibiting adenylate cyclase, which stimulates the L-type Ca current. Vagal stimulation thereby decreases AVN conduction velocity and increases AVN ERP (Figures 13, 14, and 15). A sufficiently high level of acetylcholine can cause complete AVN conduction block for several seconds until desensitization occurs (desensitization prevents continuous asystole and death from occurring).

Figure 13.Effect of autonomic tone on AV node action potential. The upstroke is generated by the L-type Ca current, which is similar in magnitude to the K currents that can be activated by ACh (ICASH). Vagal tone increases outward K-current (and suppresses Ca-current), thereby decreasing upward velocity and action potential amplitude, and increasing AV node ERP. Sympathetic tone increases Ca current amplitude, increases upward movement speed and conduction, and shortens AV node ERP.

Figure 14.Regulation of ERP in the AV node. In the AV node, the upstroke of the action potential is mediated by the L-type Ca channel. This channel shows similar voltage-dependent behavior as the Na channel, but with slower kinetics. Full recovery from inactivation typically occurs some time after full repolarization. Therefore, there is a “post-repolarization refractory period”. After a previous action potential, a critical number of Ca channels must normally recover from inactivation in order to generate a stimulus strong enough to overcome a basal K-conductance and depolarize a neighboring cell to threshold. When the number of functional Ca channels is increased (e.g., by norepinephrine), a smaller percentage of the total population of Ca channels must recover from inactivation to generate a stimulus strong enough to induce a neighboring cell bis to excite to the threshold. This shortens the AV node ERP. Neurotransmitters that increase or decrease the number of functional Ca channels can thereby alter the AV node ERP by altering the balance between the number of functional Ca channels and K channels.

Figure 15.An illustration of the cellular mechanism by which acetylcholine (ACh) can increase ERP in the AV node. The top panel shows a time point after a previous AV nodal action potential, when a sufficient number of Ca channels have recovered from inactivation and can generate a net inward current strong enough to invade a neighboring cell to threshold depolarize when stimulated by a second stimulus delivered from the atria. The lower image shows the same point in time after vagal stimulation, which produces a large increase in ICASHand a small decrease in L-type Ca current. In the presence of vagal stimulation, the cell cannot produce enough net inward current to excite a neighboring cell to threshold. This AV nodal cell would have to wait additional time for enough Ca channels to regain excitability to allow conduction to occur. This illustrates how ACh can prolong AV node ERP by increasing K conductance and decreasing Ca conductance. Norepinephrine, which stimulates Ca current, has the opposite effect on AV node ERP.

Electrophysiological basics for normal automatic (impulse formation)

automatismis defined as the ability of cardiac cells to spontaneously depolarize and generate an action potential. In a normal healthy heart, only cells in the regions of the SAN, AVN, and His-Purkinje conduction systems have the property of automaticity, or the ability to spontaneously depolarize to threshold when unstimulated. The transmembrane potential in these cells is never stable (never really "resting"). (Note that healthy ventricular muscle cells and the majority of atrial muscle cells do not show automaticity.)

Cells that can reach threshold in the shortest amount of time have the greatest automaticity because they can generate action potentials faster than other cells. It is known that diastolic depolarization underlies itAutomatism results from an imbalance between the net inward flux of positive ions (Na or Ca), which depolarizes the cell, and the outward flux of positive K ions, which hyperpolarize the cell.

Normally, cells in the SAN have the greatest automatic (rate of fire) and therefore act as a normal pacemaker for the heart. Cells outside the SAN that have the potential to become pacemakers are often referred to aslatent pacemakers. When the automatics of the SAN are decreased or the automatics of cells outside the SAN are increased and result in the generation of an action potential at a site outside the SAN, that region is referred to as oneectopic pacemaker.

  • SAN:Cells in the SAN typically beat at a rate of~70 bpmwhen the body is at rest (and under the influence of some vagal tone). Removal of vagal tone (eg, by administration of atropine, a drug that blocks "muscarinic" acetylcholine receptors) results in an increase in resting sinus rate to 20 to 30 bpm (though to a lesser extent in older patients). .

  • AVN:Cells in the AVN have an intrinsic firing rate of40 to 60 beats/minute, slightly slower than in the SA node.

  • Purkinje fibers:Cells in the Purkinje fiber region have an intrinsic firing rate of15 to 40 beats/minute.

This distribution of different automatic rates can be beneficial when conduction of the SAN becomes blocked, as can occur with SAN disease (“Sick Sinus Syndrome”) or inferior MI that blocks conduction through the AVN. Under these conditions, a new ectopic pacemaker typically develops after a brief pause. The ectopic pacemaker (derived, for example, from the AVN or Purkinje system) then drives the ventricles at a slower rate, hopefully sufficient to maintain adequate cardiac output.

Two mechanisms for normal automatics

There are differences in the ionic mechanisms underlying the automatism in the SAN and His-Purkinje systems (see Figure 16).

  • SAN: In the SAN there ismultiple sources of depolarizing inward currentduring diastole, including:

    • both T and L type Ca currents

    • a non-selective "weird" Na/K pacing current ("IF“)

IF: It's not hilarious, but it's funny

IFis a (unusual or "funny") current in that itslowactivated onHyperpolarisationnegative up to a threshold of -50 mV. It is a non-selective current for both Na and K, but is mainly conducted by Na under physiological conditions since there is little driving force for K flow at voltages near EK.NOTE:IFsometimes also referred to as "IH", where "h" stands for the designation that it is a "hyperpolarization" activated current. The two designations are interchangeable. This stream results from the expression of genes encoding theHyperpolarization-activated cyclic nucleotide-gated (HCN) channel. Four HCN genes have been identified and they are expressed in both cardiac tissue (SA node, AV node and His-Purkinje cells) and regions of the CNS. HCN4 is the main isoform expressed in cardiac tissue (Hermann et al, 2011; DeBerg et al, 2016).

  • Purkinje fibers:Purkinje fibers reach a much more negative maximum diastolic potential (see Figure 16). Ca channels are not open at such negative diastolic potentials. Consequently:

    • the source of the depolarizing current underlying phase 4 depolarization and automatics in the His-Purkinje system is solely “IF.

    • IF(IH) follows from the expression ofHyperpolarization-activated cyclic nucleotide-gated (HCN) channels. These channels are regulated by both membrane voltage (where hyperpolarization causes increased activation) and cAMP, a cyclic nucleotide.

    • Binding of cAMP increases the rate and magnitude of channel activation and shifts half the activation voltage towards less hyperpolarized voltages, resulting in greater activation of the current over the normal physiological diastolic membrane voltage range (DeBerg et al., 2016).

    • These channels have relatively slow activation kinetics and are not selective for Na and K. As a result, activation of IFresults in an inflow of Na ions greater than the outflow of K ions through K channels, resulting in slow depolarization (phase 4 depolarization) up to threshold.

Figure 16.Various ionic mechanisms for automatics in the SAN and His-Purkinje systems. The ion fluxes underlying different phases of the cardiac action potential are given for cells in the SAN and His-Purkinje systems. In the SAN, phase 4 automatics is regulated by a mixture of ionic currents, including L-type and T-type Ca currents, the decay of time-dependent K currents, and the slow activation of a hyperpolarization-activated nonselective current (IF). In Purkinje fibers, phase 4 depolarization is solely due to slow activation of IFwhich produces a depolarizing current that eventually overcomes the hyperpolarizing influence of the background K-current (IK1).


Drugs that selectively block IFsuch asIvabradin(Procoralan ®) were observed too selectivelyreduce the human heart ratearound 10-15 beats per minute at therapeutic doses, an effect that may become useful in the treatment of angina where reduced heart rate is beneficial (by reducing cardiac work and oxygen demand) (Koster et al., 2009; DiFrancesco 2010) .

Drugs that block L-type Ca channels, such as verapamil (Calan®) or diltiazem (Cardizem®) as welllead to a decrease in heart rate due to their effect on the SAN. In high doses, they can cause severe bradycardia or even asystole. Calcium channel blockers are also usedslow conduction through the AV node(they increase the PR interval) and increase the ERP of the AV node. Their action of reducing calcium influx into ventricular tissue also weakens the force of ventricular contraction - anegative inotropicSide effect. These are all expected results based on the role of calcium flux in these different regions of the heart.

ANS modulation of the automatic

Neurotransmitters such as acetylcholine and norepinephrine alter the automatics by modulating the behavior of the ion channels, which in turn alters the steepness of the slope of the diastolic (phase 4) depolarization.

Vagale Stimulationincreases the magnitude of the ligand-gated K-current (ICASH), one by muscarinic m2receptors (Figure 12). A larger efflux of K ions leads to aless steep slope of phase 4 depolarizationin both SAN and Purkinje fibers (Figure 17). This is the mechanism by which vagal stimulation reduces heart rate (sinus rate) when the body is at rest (when vagal tone is dominant). Very intense vagal stimulation can also decrease automaticity by hyperpolarizing (making it more negative) the maximum diastolic potential. (Note: Purkinje fibers are the only part of the ventricle that is under the influence of vagal innervation).

Sympathetic stimulationincreases the magnitude of both the L-type Ca current and IF. A larger influx of Ca and Na ionsleads to a steeper slope of the phase 4 depolarization, and an increase in heart rate during exercise and in fight-or-flight situations.

Note that drugs that directly or indirectly IF(Catecholamines, beta-blockers and type 1 antiarrhythmics) affect the (ectopic) Purkinje fiber automatics, but an L-type Ca channel blocker does not.

Figure 17.Effect of vagal stimulation (acetylcholine) and sympathetic stimulation (norepinephrine) on Purkinje fiber automatics.Links:Vagal stimulation increases ICASH, leading to an increase in K efflux, which offsets the I-mediated Na influxF, eliminating the automatism.To the right:Sympathetic stimulation increases IFvon

How hypokalemia improves ectopic pacemaker response

As shown in Figure 18, Purkinje fiber automatics can also be altered by changes in extracellular K concentration. Changes in [K]Öchange EK, as predicted by the Nernst equation. A reduction of [K]Öcauses both EKand the maximum diastolic potential more negative. This hyperpolarization in turn activates a larger selfF, which in turn creates a stronger depolarizing current in phase 4.Hypokalemia can thus lead to the development of ectopic pacemaker activity by leading to a steeper slope of phase 4 depolarization. Hyperkalemia does the exact opposite (i.e., it suppresses automatism).

Note that SA node cell automatics are relatively unaffected by changes in extracellular potassium concentration compared to Purkinje fibers. A summary of the variables altered by changes in extracellular potassium that alter automation is presented in Table 1.

Figure 18.The effect of extracellular K on automatics. The numbers assigned to each lane indicate the concentration of extracellular K. Extracellular K affects peak diastolic potential and automatics in Purkinje fibers but has little effect on automatics in SAN. This difference is due to the fact that Purkinje fibers have stronger K permeability, which is sensitive to changes in the K driving force. For example, in Purkinje fibers, hyperpolarization associated with hypokalemia activates a larger Ih, thereby increasing the influx of depolarizing current during phase 4. Cells in the SAN are less sensitive to changes in [K]Öbecause the "diastolic" potassium conductivity in these cells is smaller.

TABLE 1: Effect of hypokalemia on ectopic pacemaker automation

Hypokalemia increases the Purkinje automatic because:

  1. EKbecomes more negative (prediction of the Nernst equation)

  2. A more negative EKcauses the maximum diastolic Vm to become more negative

  3. A more negative diastolic Vm activates more IF, which produces an enhanced phase 4 depolarization

  4. A low [K+]Öreduced IK1; in hypokalemia, fewer K channels are open

Hyperkalemia decreases Purkinje automatics because:

  1. EKbecomes more positive (prediction of the Nernst equation)

  2. less meFis activated at more positive potentials

  3. IK1is increased by increasing [K+]Ö, resulting in the membrane potential “resting” near E.K

Excitation-contraction coupling (calcium-induced calcium release)

For the heart to function as a mechanical pump, the process of electrical stimulation must result in an increase in intracellular calcium sufficient to enhance the interaction between actin and myosin, resulting in a shortening of myocardial cell length. This process is commonly referred to as "excitation-contraction coupling". In cardiac cells, the main source of the increase in intracellular calcium that causes contraction is the rapid release of Ca from the sarcoplasmic reticulum (SR). With each heartbeat, the action potential propagates across the surface of the myocardial cells and into invaginations of the cell membrane (T-tubules), which allow excitation to spread to the interior of each myocardial cell (see Figure 19).

Figure 19.Schematic representation of the movements of Ca during excitation-contraction coupling in cardiac tissue. The influx of Ca during the action potential plateau triggers the release of Ca stored in the sarcoplasmic reticulum into the cytoplasm. The sharp increase in free cytosolic Ca activates myofilament contraction (systole). Relaxation (diastole) occurs after reuptake of cytosolic Ca into the SR via a Ca pump (SERCA) and partial extrusion of Ca into the extracellular fluid via Na/Ca exchange.

Interestingly, the amount of calcium entering the cell during the action potential plateau is not sufficient to directly cause myofibrils to contract. The trigger, however, is the calcium entering via the L-type Ca channels (trigger approx) that stimulates the neighboring SR to release a large pool of its previously stored Ca into the cytoplasm. This is done through a mechanism known asCalcium-induced calcium release. This process leads to an increase in intracellular (sarcoplasmic) Ca concentration from a diastolic value of less than 0.1 μM to a systolic value of 1 to 10 μM. The increase in calcium concentration increases the amount of Ca bound to the protein troponin C. The Ca-troponin complex then interacts with tropomyosin to unblock the active sites between actin and myosin filaments. This unblocking process allows cross-bridge interactions between the filaments and the contraction of the cell (systole). Mechanisms that increase the amount of Ca released into the cytoplasm with each beat (e.g., β-adrenergic agonists), increase contractile force (positive inotropic effect), and mechanisms that result in less Ca release during systole (e.g., B. Ca-channel blockers) reduce the force of contraction (negative inotropic effect).

At the end of the action potential, Ca influx through L-type Ca channels ceases and the SR is no longer stimulated to release Ca. The Ca released into the cytoplasm is pumped back into the SR, and the increase in total cellular Ca that occurred during the action potential plateau is removed by Na/Ca exchange (Figure 19). These events lower the cytoplasmic Ca concentration, leading to a decrease in the interaction between the myofilaments and subsequent relaxation (diastole).

Note that since the net Ca gained during each action potential is regulated by the Na/Ca exchange mechanism, events that decrease the Na concentration gradient (i.e., an increase in intracellular Na concentration in response to inhibition of Na/ K pump). Change in contractility. TherewithCardiac tissue contractility is responsive to both the amount of Ca influx, which regulates Ca-induced Ca release from the SR, and intracellular and extracellular Na concentrations(due to the role of the Na/Ca exchange mechanism in regulating intracellular Ca concentration).

The Ca-induced Ca-release mechanism allows contractilityrisen quicklyin response to sympathetically mediated stimulation of Ca influx, which occurs within seconds during "fight or flight" situations in which elevated levels of norepinephrine are released from sympathetic nerve endings, and to stimulation by adrenaline released by the adrenal gland.So when it comes to the heart, a calcium-induced calcium-release mechanism for EC-coupling most likely has survival benefits.


Herzelectrophysiology(10 questions)


  • Berdeaux A (2007): Preclinical results with If current inhibition by ivabradine. Drugs 2007; 67 (Supplement 2): 25-33.

  • DeBerg HA et al (2016): Structure and Energetics of Allosteric Regulation of HCN2 Ion Channels by Cyclic Nucleotides. JBiolChem. 291 (1): 371–381. doi: 10.1074/jbc.M115.696450

  • DiFrancesco D (2010): The role of the fun current in pacemaker activity. circulation research; 106:434-446.

  • Herrmann S et al (2011): Novel insights into the distribution of cardiac HCN channels: an expression study in the mouse heart. J Mol Cell Cardio.51(6):997-1006. doi: 10.1016/j.yjmcc.2011.09.005.

  • Harvey RD, Grant AO (2018): Agents in cardiac arrhythmias (Chapter 14). In:Basic and clinical pharmacology. 14th ed.Katzung BG (Editor). McGraw-Hill / Lange.

  • Noble D (1985): Ionic basis of rhythmic activity in the heart. Chapter 1. In: Cardiac electrophysiology and arrhythmias. Zipes DP, Jalife J (editors). Green & Stratton Inc.


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