Physio Report Script Cvs.docx

Goodafternoon, I’m Bryan Cruz and my topic is about the action potential of cardiac muscles specialized for conduction Slide 1 Although all cells in the heart can conduct action potentials, some cells are specialized for generating and propagating electrical signals through the heart and are referred to here as conducting cells. includes cells in the   

Sinoatrial (SA node) Atrioventricular node (AV node) Purkinje fibers

The conducting system of the heart consists of cardiac muscle cells and conducting fibers (not nervous tissue) that are specialized for initiating impulses and conducting them rapidly through the heart (see the image below). They initiate the normal cardiac cycle and coordinate the contractions of cardiac chambers. Both atria contract together, as do the ventricles, but atrial contraction occurs first. The conducting system provides the heart its automatic rhythmic beat. For the heart to pump efficiently and the systemic and pulmonary circulations to operate in synchrony, the events in the cardiac cycle must be coordinated

----------------Slide 2 - Overview Conduction action potentials are divided into three phases. First, there is absence of resting potential that allows them to have spontaneous depolarization and not requires neural stimulation to function   

Phase 4 is the spontaneous depolarization (pacemaker potential) that triggers the action potential once the membrane potential reaches threshold between -40 and -30 mV). Phase 0 is the depolarization phase of the action potential. This is followed by phase 3 repolarization. Once the cell is completely repolarized at about -60 mV, the cycle is spontaneously repeated.

Slide 3 - Phase 4 At the end of repolarization, when the membrane potential is very negative (about -60 mV), ion channels open that conduct slow, inward (depolarizing) Na+ currents. These currents are called "funny" currents and abbreviated as "If". These depolarizing currents cause the membrane potential to begin to spontaneously depolarize, thereby initiating Phase 4. As the membrane potential reaches about -50 mV, another type of channel opens. This channel is called transient or T-type Ca++ channel.

When the membrane depolarizes to about -40 mV, a second type of Ca++ channel opens. These are the long-lasting, or L-type Ca++ channels. Opening of these channels causes more Ca++ to enter the cell and to further depolarize the cell until an action potential threshold is reached (usually between -40 and -30 mV). It should be noted that a hyperpolarized state is necessary for pacemaker channels to become activated. Without the membrane voltage becoming very negative at the end of phase 3, pacemaker channels remain inactivated, which suppresses pacemaker currents and decreases the slope of phase 4. This is one reason why cellular hypoxia, which depolarizes the cell and alters phase 3 hyperpolarization, leads to a reduction in pacemaker rate (i.e., produces bradycardia). During Phase 4 there is also a slow decline in the outward movement of K+ as the K+ channels responsible for Phase 3 continue to close. This fall in K+ conductance (gK+) contributes to the depolarizing pacemaker potential. Slide 4 - Phase 0 Depolarization is primarily caused by increased Ca++ conductance (gCa++) through the L-type Ca++ channels that began to open toward the end of Phase 4. The "funny" currents, and Ca++ currents through the T-type Ca++ channels, decline during this phase as their respective channels close. Because the movement of Ca++ through these channels into the cell is not rapid, the rate of depolarization (slope of Phase 0) is much slower than found in other cardiac cells (e.g., Purkinje cells). Slide 5 - Phase 3 During Phase 3 repolarization occurs as K+ channels open (increased gK+) thereby increasing the outward directed, hyperpolarizing K+ currents. At the same time, the L-type Ca++ channels become inactivated and close, which decreases gCa++ and the inward depolarizing Ca++ currents. ---------------------------------------------------------Although all cells in the heart can conduct action potentials, some cells are specialized for generating and propagating electrical signals through the heart and are referred to here as conducting cells. As shown in Figure 1, this includes cells in the SA node, atrio-ventricular node (AV node), and the Purkinje fibers. These cells have relatively few myofilaments and generate only weak contractile forces. The SA node includes the normal pacemaker cells. The cells in the AV node provide the electrical gateway between the atria and the ventricles. The Purkinje fibers are the distribution network that runs through sub-endocardial space (you saw them in this Virtual Imaging Lab, Topic 8 & Topic 9). Purkinje fibers are the fastest conducting fibers in the heart, and this rapid propagation of excitation coordinates the timing of the contraction of the working myocytes in the ventricles. -------------------As you examine Figure 2, notice that depolarization starts in the SA node, travels through the atrial internodal fibers, then through the AV node and subsequent Purkinje fibers, and finally out through the working cells in the ventricles. This figure also shows variability in the shape of the action potential at each location along this path. Just as there is a division of labor between working and conducting cells,

these two distinct subpopulations of cells also produce different types of action potentials. Those action potentials can be fast and long, or slow and brief.

Fast/long action potentials are produced in working cells and Purkinje fibers. Working cells do not exhibit automaticity, and they lack a spontaneous depolarization to threshold for producing an action potential. Purkinje fibers have a fast and long action potential, like the working cells, but they also have a small degree of automaticity, which we will discuss later. The action potential is initiated by a very large Na+current produced by the opening of voltage-gated Na channels. The depolarization produced by the opening of the Na channels stimulates the opening of L-type Ca channels, which produces a long plateau in the action potential during which Ca++ enters the myocyte and contributes to contraction of the muscle. Slow/brief action potentials are produced in the SA & AV nodes. These are the cells that exhibit automaticity. Their membrane potential is never constant, and they spontaneously depolarize towards threshold to produce an action potential. The action potentials are produced by the opening of L-type Ca channels only, and the action potentials can be blocked by verapamil and diltiazem. Voltage-gated Na channels are not involved in these action potentials.

-------------------Comparing the action potential of the working myocyte to that of a pacemaker cell shown in Figure 3, notice that the shape of each is very different. Let’s repeat our dissection of the phases, this time looking at action potentials in the SA node and AV node cells. Here’s what is happening in each phase:

Phase 0: These cells do not have voltage-gated sodium channels, and the L-type calcium channels turn on more slowly with depolarization (ICa). This produces a slower upstroke of the action potential. Phases 1 & 2: These phases are not really developed in these cells. Phase 3: Repolarization of the membrane potential is produced by the opening of voltage-gated potassium channels (IK). Phase 4: The membrane potential during phase 4 is not stable, so the line is not flat. There is a spontaneous depolarization of the membrane potential towards the threshold for producing an action potential by the opening of L-type Ca channels. Phase 4 is the primary determinant of automaticity and heart rate! During phase 4 there is a “leak” current that allows Na+ to enter the cell. This is called the “funny” current, and it is labeled as If. The leakage of Na+ into the cell through the funny channels gradually depolarizes the membrane potential to the threshold for opening L-type Ca channels. This is

how a pacemaker cell makes the transition during phase 4 back to phase 0. The larger the funny current, the faster the rate of spontaneous depolarization during phase 4. The smaller the funny current, the slower the rate of spontaneous depolarization. The size of the funny current is increased by the activation of adenylyl cyclase, either as a result of an increase in the binding of cAMP to funny channels or by phosphorylation of funny channels by Protein Kinase A. Now, think about how this mechanism could account for the ability of vagal stimulation to slow the heart rate or for sympathetic stimulation (or circulating epinephrine) to increase heart rate. How does the binding of ACh to muscarinic M2 receptors affect adenylyl cyclase? How does the binding of norepinephrine or epinephrine to Beta 1 receptors affect adenylyl cyclase? Don't move on until you have made sense out of this! --------------------

Automaticity The rate of depolarization of SA node cells is faster than the rate of depolarization of AV node cells. But, if for some reason SA node depolarization slows down, AV node cells can take over as the pacemaker for the heart. Purkinje fibers also display automaticity. The funny current is regulated by Protein Kinase A (PKA), with phosphorylation increasing the size of If. This is a fundamental mechanism for regulating heart rate. ß1-adrenoreceptors stimulated by norepinephrine or epinephrine activate Gs, which increases [cAMP], activates PKA, increases If and speeds up the heart rate. Alternatively, muscarinic M2 receptors stimulated by acetylcholine activate Gi, which decreases [cAMP], decreases activation of PKA, decreases If, and slows the heart rate. Another related mechanism controlling heart rate is the increased influx of calcium through L-type calcium channels produced when these channels are phosphorylated by PKA. You should be able to figure out how this mechanism for influencing threshold is related to the regulation by ACh and the catecholamines, by analogy to the regulation of If described above. What happens if the SA node fails to reach threshold? The AV node also exhibits automaticity (40 beats/minute), and it is just a little slower than the normal SA node (>60 beats/minute). Therefore, if the SA node fails, then the AV node will reach threshold and take over as pacemaker. Given the great importance of contracting the heart, there is actually a “Plan C”. If both the SA node and AV node fail, the Purkinje fibers have a modest level of automaticity (20 beats/minute) that may still reach threshold. The activation of the AV node or the Purkinje fibers is called an Escape Rhythm, referring to the fact the heart escaped from a condition of inactivity. Healthy working cells do not demonstrate automaticity. But, if injured, they can develop automaticity. Responsiveness This is the rate of depolarization of the membrane potential during phase 0. The working cells and Purkinje fibers have a very high responsiveness because of the presence of many voltage-gated Na channels. Threshold

The membrane potential at which an action potential is triggered. Increasing the threshold corresponds to making the threshold membrane potential more depolarized and more difficult to reach. Conduction Velocity The rate of propagation of an action potential, which depends on the density of the channels carrying inward currents and the spike threshold. Purkinje fibers have the highest conduction velocity. This is important because the regions of the ventricles near the apex of the heart must contract first, or at least no later than the regions closer to the aortic and pulmonary valves. Conduction through the bundles and branches of Purkinje fibers helps to coordinate this. Refractory Period The period of time during which the threshold for producing an action potential is increased. During an absolute refractory period, an action potential cannot be produced regardless of the size of the stimulus. During the relative refractory period, an action potential can be produced, but the stimulus must be larger than normal. Refractoriness is produced by the inactivation of voltage-gated Na and Ca channels. The refractory period is terminated by the activation of voltage-gated K channels and hyperpolarization back to the resting membrane potential." The duration of the refractory period is determined primarily by the duration of the action potential, because a myocyte must repolarize to close to the resting membrane potential to regain its excitability. The most direct way to increase the refractory period is to block voltage-gated K channels and delay the repolarization to the resting membrane potential (phase 3). Refractoriness in cardiac tissue helps ensure a unidirectional propagation of action potentials through the cardiac syncytium in the same manner that refractoriness ensures the propagation of an action potential in only one direction along an axon. ---------------------Action potential and automaticity of SA node 

Cells within the sinoatrial (SA) node are the primary pacemaker site within the heart. These cells are characterized as having no true resting potential, but instead generate regular, spontaneous action potentials.

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SA nodal action potentials are divided into three phases:

1. phase 0, upstroke of the action potential; 2. phase 3, the period of repolarization; 3. and phase 4, the period of spontaneous depolarization that leads to subsequent generation of a new action potential

Overview The conducting system of the heart consists of cardiac muscle cells and conducting fibers (not nervous tissue) that are specialized for initiating impulses and conducting them rapidly through the heart (see the image below). They initiate the normal cardiac cycle and coordinate the contractions of cardiac chambers. Both atria contract together, as do the ventricles, but atrial contraction occurs first. The conducting system provides the heart its automatic rhythmic beat. For the heart to pump efficiently and the systemic and pulmonary circulations to operate in synchrony, the events in the cardiac cycle must be coordinated

Sinoatrial node Internodal and intra-atrial conduction Atrioventricular node Bundle of His Bundle branches Terminal Purkinje fibers

Step 1: Pacemaker Impulse Generation

The first step of cardiac conduction is impulse generation. The sinoatrial (SA) node (also referred to as the pacemaker of the heart) contracts, generating nerve impulses that travel throughout the heart wall. This causes both atria to contract. The SA node is located in the upper wall of the right atrium. It is composed of nodal tissue that has characteristics of both muscle and nervous tissue.

Step 2: AV Node Impulse Conduction The atrioventricular (AV) node lies on the right side of the partition that divides the atria, near the bottom of the right atrium. When the impulses from the SA node reach the AV node, they are delayed for about a tenth of a second. This delay allows atria to contract and empty their contents into the ventricles prior to ventricle contraction.

Step 3: AV Bundle Impulse Conduction The impulses are then sent down the atrioventricular bundle. This bundle of fibers branches off into two bundles and the impulses are carried down the center of the heart to the left and right ventricles.

Step 4: Purkinje Fibers Impulse Conduction At the base of the heart, the atrioventricular bundles start to divide further into Purkinje fibers. When the impulses reach these fibers they trigger the muscle fibers in the ventricles to contract. The right ventricle sends blood to the lungs via the pulmonary artery. The left ventricle pumps blood to the aorta.

Cardiac Conduction and the Cardiac Cycle Cardiac conduction is the driving force behind the cardiac cycle. This cycle is the sequence of events that occur when the heart beats. During the diastole phase of the cardiac cycle, the atria and ventricles are relaxed and blood flows into the atria and ventricles. In the systole phase, the ventricles contract sending blood to the rest of the body. ----------------------------------------------------Sinoatrial node The sinoatrial (SA) node is a spindle-shaped structure composed of a fibrous tissue matrix with closely packed cells. It is 10-20 mm long, 2-3 mm wide, and thick, tending to narrow caudally toward the inferior vena cava (IVC). The SA node is located less than 1 mm from the epicardial surface, laterally in the right atrial sulcus terminalis at the junction of the anteromedial aspect of the superior vena cava (SVC) and the right atrium (RA). The artery supplying the sinus node branches from the right coronary artery in 55-60% of hearts or the left circumflex artery in 40-45% of hearts. The artery approaches the node from a clockwise or counterclockwise direction around the SVC–RA junction.

The SA node is densely innervated with postganglionic adrenergic and cholinergic nerve terminals. Neurotransmitters modulate the SA node discharge rate by stimulation of beta-adrenergic and muscarinic receptors. Both beta1 and beta2 adrenoceptors subtypes are present in the SA node. The human SA node contains a more than 3-fold greater density of beta-adrenergic and muscarinic cholinergic receptors than the adjacent atrial tissue.

Internodal and intra-atrial conduction Anatomic evidence suggests the presence of 3 intra-atrial pathways: (1) anterior internodal pathway, (2) middle internodal tract, and (3) posterior internodal tract. The anterior internodal pathway begins at the anterior margin of the SA node and curves anteriorly around the SVC to enter the anterior interatrial band, called the Bachmann bundle (see the image below). This band continues to the left atrium (LA), with the anterior internodal pathway entering the superior margin of the AV node. The Bachmann bundle is a large muscle bundle that appears to conduct the cardiac impulse preferentially from the RA to the LA.

The middle internodal tract begins at the superior and posterior margins of the sinus node, travels behind the SVC to the crest of the interatrial septum, and descends in the interatrial septum to the superior margin of the AV node. The posterior internodal tract starts at the posterior margin of the sinus node and travels posteriorly around the SVC and along the crista terminalis to the eustachian ridge and then into the interatrial septum above the coronary sinus, where it joins the posterior portion of the AV node. These groups of internodal tissue are best referred to as internodal atrial myocardium, not tracts, as they do not appear to be histologically discrete specialized tracts. Atrioventricular node The compact portion of the atrioventricular (AV) node is a superficial structure located just beneath the RA endocardium, anterior to the ostium of the coronary sinus, and directly above the insertion of the septal leaflet of the tricuspid valve. It is at the apex of a triangle formed by the tricuspid annulus and the tendon of Todaro, which originates in the central fibrous body and passes posteriorly through the atrial septum to continue with the eustachian valve The stippled area adjacent to the central fibrous The stippled area adjacent to the central fibrous body is the approximate site of the compact atrioventricular node. Drawing of a normal human heart showing the anatomic landmarks of the triangle of Koch. This triangle is delimited by the tendon of Todaro superiorly, the fibrous commissure of the flap guarding the openings of the inferior vena cava and coronary sinus, by the attachment of the septal leaflet of the tricuspid valve inferiorly, and by the mouth of the coronary sinus at the base.

In 85-90% of human hearts, the arterial supply to the AV node is a branch from the right coronary artery that originates at the posterior intersection of the AV and interventricular grooves (crux). In the remaining 10-15% of the hearts, a branch of the left circumflex coronary artery provides the AV nodal artery. Fibers in the lower part of the AV node may exhibit automatic impulse formation. The main function of the AV node is modulation of the atrial impulse transmission to the ventricles to coordinate atrial and ventricular contractions.

Bundle of His The bundle of His is a structure that connects with the distal part of the compact AV node, perforates the central fibrous body, and continues through the annulus fibrosus, where it is called the nonbranching portion as it penetrates the membranous septum. Connective tissue of the central fibrous body and membranous septum encloses the penetrating portion of the AV bundle, which may send out extensions into the central fibrous body. Proximal cells of the penetrating portion are heterogeneous and resemble those of the compact AV node; distal cells are similar to cells in the proximal bundle branches. Branches from the anterior and posterior descending coronary arteries supply the upper muscular interventricular septum with blood, which makes the conduction system at this site more impervious to the ischemic damage, unless the ischemia is extensive.

Bundle branches The bundle branches originate at the superior margin of the muscular interventricular septum, immediately below the membranous septum, with the cells of the left bundle branch cascading downward as a continuous sheet onto the septum beneath the noncoronary aortic cusp. The right bundle branch continues intramyocardially as an unbranched extension of the AV bundle down the right side of the interventricular septum to the apex of the right ventricle and base of the anterior papillary muscle. The anatomy of the left bundle branch system may be variable and may not conform to a constant bifascicular division. However, for clinical purposes and electrocardiography (ECG), the concept of a trifascicular system remains useful (see the images below)

Schematic representation of the trifascicular bund Schematic representation of the trifascicular bundle branch system. A = anterior fascicle of left bundle branch; AVN = atrioventricular node; HB = bundle of His; LBB = left bundle branch; RBB = right bundle branch; P = posterior fascicle of left bundle branch. Structural organization of the His-Purkinje system Structural organization of the His-Purkinje system in mouse heart. Expression of a green fluorescent protein was specifically targeted to cells of the His-Purkinje system in mice. Green fluorescent cell networks in the left ventricular chamber are shown. The left ventricular free wall (LVW) was incised from base to apex, and then the 2 parts of the LVW were pulled back to expose the left flank of the

interventricular septum (LF). The dotted line demarcates the border between the LF and the LVW.A = anterosuperior fascicle of the left bundle; AVN = atrioventricular node; HB = His bundle: LBB = left bundle branch; P = posteroinferior fascicle of the left bundle branch: RBB = right bundle branch: PF = Purkinje fiber. Terminal Purkinje fibers The terminal Purkinje fibers connect with the ends of the bundle branches to form interweaving networks on the endocardial surface of both ventricles, which transmit the cardiac impulse almost simultaneously to the entire right and left ventricular endocardium. Purkinje fibers tend to be less concentrated at the base of the ventricle and the papillary muscle tips. They penetrate only the inner third of the endocardium. Purkinje fibers appear to be more resistant to ischemia than ordinary myocardial fibers.

Innervation of the AV node, His bundle, and ventricular myocardium The AV node and His bundle are innervated by a rich supply of cholinergic and adrenergic fibers with higher densities as compared with the ventricular myocardium. Parasympathetic nerves to the AV node region enter the heart at the junction of the IVC and the inferior aspect of the LA, adjacent to the coronary sinus ostium.

The autonomic neural input to the heart demonstrates some degree of "sidedness," with the right sympathetic and vagal nerves affecting the SA node more than the AV node and the left sympathetic and vagal nerves affecting the AV node more than the SA node. The distribution of the neural input to the SA and AV nodes is complex because of substantial overlapping innervation.

Stimulation of the right stellate ganglion produces sinus tachycardia with less effect on AV nodal conduction, whereas stimulation of the left stellate ganglion generally produces a shift in the sinus pacemaker to an ectopic site and consistently shortens AV nodal conduction time and refractoriness, but it inconsistently speeds the SA node discharge rate. However, stimulation of the right cervical vagus nerve slows the SA node discharge rate, and stimulation of the left vagus primarily prolongs AV nodal conduction time and refractoriness when sidedness is present. Neither sympathetic nor vagal stimulation affects normal conduction in the His bundle. [3, 4]

Natural Variants The right vagus nerve primarily innervates the sinoatrial (SA) node, whereas the left vagus innervates the atrioventricular (AV) node; however, significant overlap can exist in the anatomic distribution.

Effects of sympathetic stimulation

Stimulation of sympathetic ganglia shortens the refractory period equally in the epicardium and underlying endocardium of the left ventricular free wall, although dispersion of recovery properties occurs (ie, different degrees of shortening of refractoriness occur) when measured at different epicardial sites. Nonuniform distribution of norepinephrine (NE) may, in part, contribute to some of the nonuniform electrophysiologic effects, because the ventricular content of NE is greater at the base than at the apex of the heart, with greater distribution to muscle than to Purkinje fibers. Afferent vagal activity appears to be higher in the posterior ventricular myocardium, which may account for the vagomimetic effects of inferior myocardial infarction. [4, 8]

Effects of vagal stimulation The vagus modulates cardiac sympathetic activity at prejunctional and postjunctional sites by regulating the amount of NE released and by inhibiting cyclic adenosine monophosphate (cAMP) – induced phosphorylation of cardiac proteins. Tonic vagal stimulation results in a greater absolute reduction in sinus rate in the presence of tonic background sympathetic stimulation. In contrast, changes in AV conduction during concomitant sympathetic and vagal stimulation are essentially the algebraic sum of the individual AV conduction responses to tonic vagal and sympathetic stimulation alone.

Cardiac responses to brief vagal bursts commence after a short latency and dissipate quickly; conversely, cardiac responses to sympathetic stimulation begin and dissipate slowly. The rapid onset and offset of responses to vagal stimulation allow dynamic beat-to-beat vagal modulation of heart rate and AV conduction, whereas the slow temporal response to sympathetic stimulation precludes any beat-to-beat regulation by sympathetic activity. Because the peak vagal effects on sinus rate and AV nodal conduction occur at different times in the cardiac cycle, a brief vagal burst can slow the sinus rate without affecting AV nodal conduction or can prolong AV nodal conduction time and not slow the sinus rate.

Increased Ca++ conductance (gca++) "Funny" currents, and Ca++ currents T-type Ca++ channels, decline Channels close. Not rapid Slower