Cardio P1 Electrophysiology of the heart.pdf

Cardiovascular Block Electrophysiology of the Heart Dr Simon Harrison [email protected] Room S3-76 1 1  LOs: Elecrophysiology and E-C coupling in the heart 1. Describe the different phases...

Cardiovascular Block Electrophysiology of the Heart Dr Simon Harrison [email protected] Room S3-76 1 1  LOs: Elecrophysiology and E-C coupling in the heart 1. Describe the different phases of the slow and fast response action potentials in the heart including the ion channels responsible for the changes in membrane potential as well as transmural differences in ventricular action potential shape and duration. 2. List the steps in excitation-contraction coupling in cardiac muscle and describe the roles of the individual components involved in the regulation of calcium. 3. Identify differences and similarities between cardiac muscle and skeletal muscle. 4. Describe the roles of ATP in cardiac muscle contraction and relaxation and the primary energy sources utilized by cardiac muscle in normal and disease states. 5. Contrast the duration of the action potential and the refractory period in ventricular muscle, a skeletal muscle, and a nerve. Explain what accounts for the long duration of the ventricular action potential and the resultant long- refractory period. Describe the advantages of the long plateau of the cardiac action potential and the long refractory period and explain why cardiac muscle cannot remain in a state of sustained (tetanic) contraction. 6. Describe the relationship between muscle length and force development in cardiac muscle. Describe the molecular origin of passive, active and total force. Understand the molecular mechanism for this based on the sliding filament theory. Describe the Frank Starling law and how the resting length of cardiac muscle is set at rest below the optimal length for tension generation unlike skeletal muscle. 7. Be able to draw the relationship between afterload and shortening velocity in cardiac muscle. On the diagram show how an increase in contractility or preload changes the relationship between afterload and the velocity of shortening. 2 Excellent review on SA node anatomy and Physiology: http://www.cardresp.fmed.edu.uy/Boyett_2010_review.pdf Supplemental (optional) reading materials: Physiology. Berne et al., Textbook of Medical Physiology, Guyton & Hall Youtube Videos: http://www.youtube.com/watch?v=0TU9PgGYhQo http://www.youtube.com/watch?v=xpR8d9KsUrQ http://www.youtube.com/watch?v=1KXZ0Tcxozo http://www.youtube.com/watch?v=v3b-YhZmQu8 http://www.youtube.com/watch?v=OnCo_e2QIAc 2  Conduction & Contractile Cells of the Heart SA and AV NODE : VENTRICULAR Pacemaker cells MUSCLE (MYOCYTES): (modified myocytes), contractile myocardial which produce the cells, which produce the slow response action fast response action potentials potential 1 2 0 3 0 3 4 4 4 4 LO1 3 The heart is autorhythmic i.e. it beats without any nervous system innervation because of the presence of specialized cells that have intrinsic electrical (pacemaker) activity. Cells of the sinoatrial (SA) node set the frequency of action potential generation because they lack a stable membrane potential between successive action potentials and instead the membrane potential displays a progressive slow depolarization, called the pacemaker potential during phase 4. The cells of the SA node initiate the action potential at a rate of approximately 60- 100 times per minute and as this cell type generates action potentials at a faster rate than other pacemaker cells present in the heart (e.g. AV nodal cells) then the SA node is considered to be the primary pacemaker of the heart. This is caused by a more rapid rate of phase 4 depolarization than in any other cardiac cell type. The action potential spreads away from the SA node throughout the atria (to the left atrium via Bachmanns bundle) at a rate of approx. 1 m/s (as adjacent cells are electrically coupled via gap junctions) and to the AV node via the internodal pathway. The conduction velocity through the AV node is much slower (0.05 m/s) which introduces a delay of approx. 100 ms between atrial excitation and ventricular excitation. This delay is functionally very important as it allows the atria to contract before the ventricles are excited which increases ventricular filling with blood. On emerging from the AV node the action potential (AP) spreads rapidly down the bundle of His, the left and right bundle branches to the apex of the heart and then up the walls of the ventricles via the Purkinje fiber network. 3 Ionic gradients across heart cell membranes Ionic gradients exist for the following ions: Extracellular: Na+ 140 mM, K+ 5 mM, Ca2+ 2 mM Intracellular: Na+ 14 mM, K+ 150 mM, Ca2+ 0.0001 mM Relative permeability to different ions is very important in influencing the membrane potential For Na+, ENa = +60 mV (+0.06 V) For K+, EK = -90 mV (-0.09 V) For Ca2+, ECa = +130 mV (+0.13 V) LO1 4 So if the membrane was only permeable to sodium (Na+), then the membrane potential would equal or be very close to the Nernst potential for sodium i.e. +60 mV. If only permeable to potassium (K+) then the membrane potential would be very close to the Nernst potential for K+ i.e. -90 mV. Similarly for Ca2+, membrane potential would be +130 mV, i.e. the Nernst potential for Ca2+. It follows that if the membrane was permeable to say both Na+ and K+, then depending on the relative permeability to the two ions, you could achieve any voltage between EK and ENa i.e. between -90 mV and +60 mV. This is what happens during an action potential. The relative permeability of the membrane to ions changes generating changes in membrane potential. If the concentrations of ions change- i.e. the magnitude of the concentration gradient, then you would need to recalculate the Nernst potential for the new conditions and therefore membrane potential would also change. 4  Cardiac ion channels Greater than 300 different ion channels in the human genome The electrical properties of a tissue depend on which ion channels are expressed in the membrane. In cardiac muscle, the main channels involved in membrane excitation are for Na+, K+ and Ca2+ ions. Some channels are not selective for one particular ion. In this case the Nernst or reversal potential of the current will reflect the relative permeability of all permeant ions. Therefore, a channel with mixed but equal permeability for both Na+ and K+ has a reversal potential between the Nernst potentials of those ions (Na+,+60 mV; K+, -90 mV) i.e. -90 x 0.5 + +60 x 0.5 = -45 + +30 mV = -15 mV. LO1 5 Ions are charged species and so are excluded from the membrane bilayer. To facilitate their movement across membranes specialized proteins are required- these are called ion channels and when open, ions can pass through them from one side of the membrane to the other down their concentration gradient. Most ion channels are essentially specific for a particular ion but others allow more than one ion to pass through- the latter are called mixed conductance channels. - we need ion channels for action potential - properties of tissues depend on which channels are expresses in the membrane - k. na , ca are needed for the hearts action potential 5  Cardiac ion channels for Na+ The fast voltage gated Na+ channel- similar to that found in muscle and neural tissue Opens at negative voltages (e.g. –70 mV) and are voltage gated Activates rapidly (opening of m gate) and then inactivates rapidly (slower closure of h gates) which closes the channel despite the activation gate still being open. Na+ enters the cell down its concentration gradient- this generates an inward membrane current. h This depolarizes the cell (i.e. makes m the cell interior more positive). Confers a very rapid upstroke to the action potential 6 Large inwardly directed electro-chemical gradient for Na ions and so when channels open, ions will enter the cell. This takes positive charge into the cell which will make the interior less negative, i.e. more positive which is called depolarizing the cell. REVIEW: the role of the m (activation) and h (inactivation) gates in Na channel activation and inactivation. Remember BOTH gates need to be open to allow Na+ entry into the cell. At the normal resting membrane potential, the activation gate (m gate) is closed and the inactivation gate (h gate) is open. In this condition the channel is functionally closed, but can be activated by a depolarization of the membrane that exceeds threshold potential. In response to such a depolarization the activation gate (m gate) opens rapidly allowing Na+ ions to enter the cell down their electrochemical gradient. This depolarization, as well as opening the activation gate also initiates the closure of the inactivation gate (h gate) but the inactivation gate closes more slowly than the activation gate opens, so there is a brief period of time (1-2 ms) during the upstroke (phase 0) of the action potential when both the activation and inactivation gates are open.. During repolarization of the action potential (phase 3) the inactivation gate (h gate) is closed but the activation gate is still open. In this condition, Na+ cannot move through the channel (despite the open activation gate). In this configuration the channels cannot be reactivated until the resting membrane potential is achieved (phase 4 in atrial and ventricular tissue) so the channels are in a refractory state. With completion of repolarization and the re-establishment of the resting membrane potential, the activation gate closes and the inactivation gate opens and the channel can then be re-activated and generation of a new action potential is now possible. - it takes about 2 milliseconds for the h gate to open and close 6  Cardiac ion channels for K+ K+ currents are outward and make the cell more negative inside when they flow (repolarization). There are 3 different K+ channels in cardiac muscle which allow outward K+ current to flow at various times during the action potential (AP). 1) Inward rectifier (Kir 2.1). Underlies stable resting potential 2) Transient outward K+ current (Ito) Underlies rapid repolarization 3) Delayed rectifier K+ current (Underlies repolarization) Delayed rectifier currents underlie action potential repolarization LO1 7 Inward rectifier acts as a background K+ channel: This channel opens at negative membrane potentials and sets the stable negative resting membrane potential of atrial and ventricular muscle close to the Nernst potential for potassium. As membrane potential becomes more positive these channels shut. Transient outward potassium current Opens rapidly upon depolarization of the membrane but closes quite rapidly too so generates a transient repolarizing force in ventricular and atrial muscle. Delayed rectifier K+ channels: Closed at negative voltages. Open when membrane potential becomes more positive and so these channels are mainly responsible for the repolarization of action potentials in the heart ; the inward rectifier the K ions move outside - transient outward K current : brief repolarization 7  Cardiac ion channels for Ca2+ 2 types: T-type and L-type- (the latter predominates) 1) T-type (Tiny conductance & Transient openings) Found predominately in pacemaker (inc PFs) and atrial tissue (not in ventricle) Open at -55 mV and inactivate rapidly Relatively small conductance compared to L-type 2) L-Type (Large conductance and Long Lasting openings) Found throughout the heart Open at -40 mV and inactivate more slowly than T-type Ca2+ enters cell depolarizing membrane (inward current). LO1 8 T type (Cav 3.1) stands for Tiny and Transient Openings of these channels, which have a small conductance therefore slowly depolarize the cells. T-type Ca channels are found in the SAN, AVN, atrial tissue and Purkinje fibers. In contrast L (Cav 1.2) stands for Large and Long lasting openings of the channels which leads to a greater flux of Ca2+ across the membrane and therefore a more rapid depolarization. L-type Ca channels are expressed throughout the tissues of the heart. - the T channels open and close quickly ( we find them in pacemaker tissue ) - they are not seen in ventricle - since they open for a smalll period of time they allow only a small amount of calcium , so it doest contribute much for the membrane potential - the L type open for a longer time than T type 8  Mixed conductance channels Funny current (If ): Confers slow depolarization in pacemaker tissue Channels permeable to Na+ and K+, (Erev close to -20 mV) Activated by hyperpolarization (i.e. at negative membrane potentials) and cAMP Driving force on an ion = difference between membrane potential and Nernst potential for that ion At membrane potential of -60 mV, driving force for Na+ influx greater than for K+ efflux Therefore net inward Na+ current Small conductance channel LO1 9 If encoded by HCN1-4, Hyperpolarisation activated Cyclic Nucleotide-gated channels Small conductance (1pS), activates slowly by hyperpolarization- that was the reason it was called the funny current as all other currents discovered at that time were activated by depolarization. Expressed in nodal and Purkinje tissues and also gated by cAMP. As a small conductance channel when open it only leads to slow changes in membrane potential. The driving force for an ion is the difference between the Nernst potential for that ion and the membrane potential. So consider the Nernst potential for Na+ (+60 mV) and K+ (-90 mV). At a membrane potential of -60 mV the driving force for efflux of K+ from the cells is the difference between -90 and -60 mV = 30 mV of driving force. For Na+ the driving force for influx of Na+ into the cells is the difference between the Nernst potential for Na+, and the membrane potential. Therefore the difference between +60 and -60 mV = 120 mV of driving force (i.e. 4 x the driving force for the exit of K+ from the cell). This is why at negative membrane potentials when the funny current opens, the current that flows is mainly an inward sodium current. - this is the channel that allows sodium and potassium in - the volatage gated channels are usually are activated by depolarization - but this channel is activated by hyperpolarization and cAMP - if there is high cAMP then there is high hyperpolarization - if there is low cAMP there would be still hyperpolarization but less - the driving force is the difference between the membrane potential and the equilibrium potential of the ion - we have a net inward Na + current - small conductance affect the membrane potential slightly 9  Sodium/Calcium exchange (NCX) Main route for efflux of Ca2+ from the cell OUT 3 Na+ ions enter the cell in exchange for 1 Ca2+ ion 3 positive charges enter the cell and 2 positive IN charges leave Electrogenic- generates current. Direction of current determined by movement of Na+ Na+ entry and Ca2+ efflux = inward membrane current Na+ removed from the cell by Na+-K+ ATPase LO1 10 See later slides on excitation-contraction coupling for more information - we use this channel to keep calcium against its concentration gradient - ELECTROGENIC **** 10  Ionic basis of the SA node action potential In SA node, inward rectifier K+ channels and fast Na + channels are absent. Therefore, these cells do not have a stable resting membrane potential during phase 4. Maximum diastolic potential of approx. -60 mV. Phase 0 Upstroke Slow depolarization or Phase 3 Repolarisation pacemaker potential towards Phase 4 Period between action threshold of approx. -40 mV potentials LO1 11 (phase 4). Phase 0 Upstroke Phase 3 Repolarisation Phase 4 Period between successive action potentials The ionic basis of the AV node is effectively the same as that for the SA node. - since there is no stable resting membrane potential then there is no inward rectifier potassium channels - phase 4 is the time between successive action potentials - phase 0 is the upstroke - phase 3 is the repolarization 11  Ionic basis of the SA Nodal Action Potential (slow response) 0: Slow upstroke (5 V/s): Opening of L-type Ca2+ channels and Influx of Ca2+ calcium is moving down its conc gradient into the cells 3: Repolarization: At +ve voltages opening of delayed K currents, efflux of K+, closure of Ca2+ channels - the cells becomes more negative since there are more potassium ions leaving 4: Pacemaker potential: the cell Closure of delayed K+ channels Opening of Funny (If) channels and slow influx of Na+ (depolarizing) At -55 mV opening of T-type Ca2+ channels and when threshold of -40 mV reached opening of L- type Ca2+ channels generating upstroke of next AP. the cell cant go lower than -60 LO1 12 the funny channels are activated hy the hyperpolarization ( they detect that the cell is at -60 adn cant get lower than that so they get activated Ionic basis of the SA nodal action potential (AV node essentially has the same ionic basis) at -55 : the l type calcium begin opening and closing , and as the repolarization starts the if shuts Nodal cells (or slow response action potentials) are produced primarily by the pacemaker cells located in the sinoatrial (SA) node and atrioventricular (AV) node) of the heart. These cells have no true resting membrane potential, rather the most negative the membrane potential becomes is called the maximum diastolic potential. SA nodal cells generate regular, spontaneous (automatic) action potentials due to the phase 4 pacemaker potential described below. - the sodium calcium channel contributes a little in this process Phase 0 (upstroke 5 V/s) - produced by the opening of voltage-dependent L-type Ca2+ channels (influx of Ca2+)- threshold of -40 mV. Phase 3 (Repolarization) - produced by the closure of L-type Ca2+ channels and opening of delayed rectifier K+ channels. Phase 4 (pacemaker potential) – As the membrane potential becomes more negative due to loss of K+ through delayed K channels, this leads to the closure of these ion channels and the opening of funny channels which are activated by the negative membrane voltage allowing a net Na+ influx which opposes the decaying outward K+ current and stops the membrane potential becoming any more negative than -60 mV, the so called maximum diastolic potential (MDP). As the funny current continues to flow, membrane potential becomes more positive as Na+ continues to enter and at approximately -55 mV T-type Ca2+ channels also start to open which continues the depolarization until the threshold of -40 mV is reached and L-type Ca2+ channels open and generate the upstroke (phase 0) of the SA node action potential. Note that the small increase in cytoplasmic calcium during phase 4 will also activate Na/Ca exchange to extrude the calcium which generates a further small inward current carried by sodium. Re Ca2+ channels: T stands for Tiny and Transient Openings of these channels, which have a small conductance therefore slowly depolarize the cells. In contrast L stands for Large and Long lasting openings of the channels which leads to a greater flux of Ca2+ across the membrane and therefore a more rapid depolarization 12  Generation of action potentials in cardiac muscle: Automaticity in the Heart Activation of T-Type Activation of T-Type Ca2+ channels Ca2+ channels LO1 13 In this slide you can see that the membrane potential in SA nodal cells is never stable, but changes continuously. Cells that display these characteristics have the capacity to act as pacemaker cells and generate action potentials which can be conducted throughout a tissue. In the case of the heart, these action potentials spread rapidly away from the SA node and innervate the atrial and ventricular tissue. - this is what it would look like if you detect the changes happening during action potential 13 the rapid upstroke is 200 times faster than SA node the plateau phase you have calcium coming in , we have a balance between the potassium and calcium slowing the process down - Ionic Basis of Ventricular Action Potential (fast response) 1 2 0: Rapid upstroke (200 V/s): rectified k channels Opening of fast voltage dependent Na+ channels and influx of Na+ 0 3 1: Phase 1 Early Repolarization: backward channels Opening of rapid, transient outward K+ channels 4 4 (Ito) and Na+ channels inactivate - Efflux K+ 2: Plateau Phase: Opening of L-type Ca2+ channels and delayed K+ channels - balance between Ca2+ influx and efflux of K+. Inward NCX current associated with removal of Ca2+. 3: Rapid Repolarization: L-type Ca2+ channels closing but delayed K+ channels still open so efflux of K+ dominates 4: Resting membrane potential: Inward rectifier K+ channels open (K+ efflux) to maintain resting membrane potential. LO1 14 Fast-response (ventricular/atrial myocyte) action potential The Fast Response (non-pacemaker) action potential is seen in contractile muscle cells (atrial and ventricular) and is commonly divided into five phases. The start of the action potential looks like the start of an action potential in a nerve or skeletal muscle cell. However, shortly after the membrane begins to repolarize, there is a long plateau phase which differs from that of neural tissue or skeletal muscle. Phase 0 (depolarization) During phase 0 the cells are most permeable to Na+, and the membrane potential depolarises towards ENa (+60 mV). Na+ channels inactivate rapidly (1-3 ms) and then remain closed until membrane potential returns to a negative voltage (-70 mV). As membrane potential becomes more positive during the upstroke, the inward rectifier K+ channels shut. This reduces the permeability of the cell membrane to K+. Phase 1 (early repolarization) - produced by the closure of fast voltage-dependant Na+ channels and the opening of fast K+ channels (transient outward K+ channels). Membrane most permeable to Potassium leading to efflux of K+ ). Phase 2 (plateau) - produced by the opening of voltage-dependant slow L-type Ca2+ channels (influx of Ca2+); the downward slope during this phase is produced by opening of the delayed K+ channels and efflux of K+). At this point there is a balance between depolarizing inward calcium current and repolarizing outward potassium current so there is mixed conductance to these two ions and therefore the plateau voltage is determined by the relative permeability to each ion. During the plateau phase the membrane potential changes only slowly. As a consequence of the increase in Ca2+ in the cells, inward current carried by NCX (which would be net sodium current- 3Na+ for every 1 Ca2+) also contributes to maintaining the plateau phase. Phase 3 (rapid repolarization) - produced by the closure of L-type Ca2+ channels and the opening of delayed K+ channels (efflux of K+); the delayed K channels repolarize the membrane down to about -60 mV when they close but at this negative voltage the inward rectifier K+ current opens and this completes the final phase of repolarization. Phase 4 (resting membrane potential) – both delayed K+ rectifier channels have closed, but the inward K+ rectifier channels (efflux of K+) remain open and maintain the resting membrane potential close to the Nernst potential for K+ (-90 mV). 14 Transmural differences in Ventricular AP duration Epicardial APs are shorter in duration than Endocardial APs in ventricles Greater expression of Ito in epicardium Gives marked phase 1 repolarization and spike and dome configuration Depolarization spreads Endo to Epi Repolarization spreads Epi to Endo LO1 15 Flaim , Giles , McCulloch American Journal of Physiology - Heart and Circulatory Physiology. Published 1 December 2006 Vol. 291 no. 6, H2617-H2629 - not all ventricular cells are the same - the epicardium has shorter duration of action potential than endocardium because epi have much more potassium channels expressed than endocardium - the epicardium of the endocardium starts first then it is sent to the epicardium by ID - so the exitation is from endo to epi - the epi repolarize first then endo - since it is shorter in epi - it helps maintain the transmural gradient ****** 15  - tetanize : an action potential building on another action potential - the long refractory period helps the cardiac muscle not to tetanize - to open the inactivation gate we have to have the membrane potential down to -75 Cardiac Muscle: ARP and RRP In cardiac muscle, AP duration (and refractory period or refractoriness) is approx. as long as contractile phase so RRP summation cannot occur. For every period of systole, there is a period of diastole, during which the heart fills with blood. Absolute Refractory Period: Another AP cannot be generated Relative Refractory Period: Another AP can be generated but the stimulus required is larger than normal to lead to a propagated AP. Refractoriness of ventricular muscle is due to a characteristic of the Fast Na+ Channels LO5 16 Cardiac muscle contractions, in contrast to skeletal muscle, cannot summate because the action potentials in cardiac muscle are of much longer duration (200-350 msec) and therefore the refractory period is also much longer. The refractory period is due to a characteristic of the fast sodium current which inactivates rapidly at the start of the ventricular action potential but does not become reactivated again until negative membrane potentials (approx -70 mV) are achieved during the repolarization of the AP. So until this membrane potential is achieved the tissue is refractory and no further APs can be generated. This period of refractoriness is known as the Absolute Refractory Period. However, towards the later stages of repolarization an action potential (AP) can be initiated but a larger than normal stimulus will be required which generates a smaller than usual AP. This is the period called the Relative Refractory Period (or RRP) since it is difficult to initiate another action potential during the repolarization period, it is difficult to initiate another contraction. This means that one contraction cannot build on the previous contraction. Physiologically this is important because it means that for every contraction period (systole), there is a resting period (diastole), during which the heart can refill with blood. 1. Absolute refractory period - the period of time during which no action potential can be initiated, regardless of stimulus strength (ARP in Figure above) and is considerably longer in duration than observed in skeletal muscle. 2. Effective refractory period, the period of time during which no propagated action potentials can be elicited regardless of stimulus strength (i.e. an action potential could be generated but it would not propagate to adjacent tissue). 3. Relative refractory period (RRP) the period of time in which a propagated response can be elicited but the stimulus required is larger than normal and the amplitude of the action potential is abnormally small. 4. Supranormal period (SNP): This can occur in circumstances where the ventricular tissue is more depolarized than normal- a hyper-excitable state and therefore a slightly smaller than normal stimulus can elicit a propagated response, although the amplitude of the action potential is reduced 16 compared to normal. This can lead to the generation of abnormally timed action potentials and ventricular (or atrial) dysrhythmia. 16 Intrinsic Pacemaker Activity of the Heart: Overdrive Suppression 60–100 bpm  SA Node – normal pacemaker 40–60 bpm  AV Node 20–40 bpm  Purkinje System LO1 17 The cells of the SA node are the first cells in the heart to generate an action potential and their frequency of firing (60-100 bpm) dominates the frequency of any other cell, thus they are referred to as the primary pacemaker cells of the heart. This is due to a more rapid rate of phase 4 depolarization than in any other cardiac cell type. Since the intrinsic firing frequencies of the secondary (atrioventricular (AV) node) and tertiary pacemakers (bundle branches and Purkinje fibers) are slower than the SA node, all the pacemakers end up firing at the SA node rate, not their own rate because their pacemaker activity will be reset by the passage of the SA node generated action potential. This rapid firing of the SA node causes the secondary and tertiary pacemakers to fire faster than their intrinsic rates. This is called overdrive-suppression. The figure above shows the time for the spread of an action potential generated in the SA node throughout the tissues of the heart. Note the different action potential waveforms in the different tissues of the heart and how these lead to the generation of the characteristic waves on the ECG (See ECG lecture 1). - if the SA node fails then we have to depend on the AV node , - purkinje node is the tertiary nodes in the ventricles - when the SA node receive the AP it resets the AV node - the purkinje node doesnt have a stable AP due to IF - any cell that has IF can be a pacemaker The atrium has a shorter duration of AP due to less L type calcium channels 17