Initiation of the Heart Beat-MBBS1-2022 PDF

Hello my name is Professor Mike Shattock and welcome to my lecture on The initiation of the Heart Beat. This lecture is about the cardiac pacemaker and the electrical events that precede mechanical contraction. The lecture is divided into 3 mini lectures - which you can see listed on the left hand...

Hello my name is Professor Mike Shattock and welcome to my lecture on The initiation of the Heart Beat. This lecture is about the cardiac pacemaker and the electrical events that precede mechanical contraction. The lecture is divided into 3 mini lectures - which you can see listed on the left hand side of this slide. In the first part we will consider why we have the heart rate we do and how this is related to body size? In the 2nd mini-lecture I will describe how heart rate is controlled and the cellular physiology of the cardiac pacemaker - the sinoatrial node. In the final mini-lecture, we will discuss the spread of excitation and the ECG. You can navigate directly to the start of each mini-lecture using the chapter markers that appear if you hover your cursor over the top left corner of the video window. On the right hand side of the slide you can see the learning objectives for this lecture. 1 In this slide you can see the lecture plan for the three mini lectures. 2 In this first lecture we're going to start by considering some of the basic principles of the circulation that determine the resting heart rate and how heart rate relates to body size and oxyen requirement. 3 So, let's think for a second, about why we have the heart rate we have? Let's just go around these rather simple slides relating body mass to various physiological variables. In Panel A, you can see the relationship between body mass and oxygen consumption of that animal. These four graphs are taken from measurements made in birds but the reality is the same for pretty much all animals and definitely all mammals. In Panel A, you can see as an animal gets bigger, not surprisingly, its total oxygen consumption (in millilitres per minute) goes up pretty linearly as a function of the log of the body mass. So, that's not really surprising. The bigger we are, the more oxygen we need. In Panel B you can see that as our oxygen demand goes up with body mass so does our cardiac output - again with a very linear relationship as a function of the logarithm of the body mass. So, cardiac output is essentially proportional to the oxygen demands of the body. Now, if we're going to have a bigger body mass and a bigger cardiac output, we also need a bigger heart. So, in Panel C, you can see again this 4 nice very consistent relationship between now body mass and heart mass - the bigger the animal, the more oxygen it consumes, the more cardiac output it needs, and the larger heart it needs in order to supply the demands of the tissues. But he's a slightly weird one in Panel D. As our hearts get bigger, heart rate decreases. As your heart gets bigger the amount of blood that is filling the heart (or filling the ventricle) is also going to get bigger. A small animal, like a mouse, has a stroke volume of just about 50 or 60 microliters. So a very small blood volume is ejected from the heart with each beat. If you imagine the inertia involved to move 60 microliters of blood very rapidly backwards and forwards you can afford to have quite a high heart rate. But if you imagine a really large animal like a whale - a blue whale has a stroke volume of about 80 litres! 80 litres of blood is pumped out of a blue whale heart with every beat. Now imagine the inertia in that. How long does it take to get 80 litres of blood to fill a ventricle and then to eject it? Think about how long it takes to put about half that amount of petrol into your car! Could you do that 600 times a minute like a mouse? Well no! It's just has too much inertia in the system. So as hearts get bigger (and they have to fill with more blood) there are some basic physical constraints as to how fast those hearts can beat. So whilst the cardiac output is going up, it does so by making the stroke volume bigger. But as the stroke volume gets bigger, the inertia in the system means that the heart rate has to slow down. In the next slide, you will see that larger animals tend to have slower heart rates. I think this is because the ventricle has to take more time to fill in between beats because of the inertia in the blood as it moves into, and out of, the ventricle. ‹#› This problem with inertia and ventricular filling is also seen in our hearts at high heart rates. in this slide volunteers were exercised up to their maximum exercise capacity and this is shown as oxygen consumption on the X axis. You can see that at higher levels of exercise, when heart rate is high, the stroke volume reaches a plateau, and at really high heart rates on the right hand side of this graph, stroke volume starts to fall. This is because at high heart rates there is not enough time in between beats to allow the ventricle to fill. You can see this in the graph on the right hand side which shows how end diastolic volume follows the same pattern - that is, in the blue shaded area, as heart rate is increasing the ventricle does not have time to fill properly and eventually this leads to the fall in stroke volume that you see on the left. 5 This is another example of the same phenomenon this time this is an paced dog hearts. Again you can see as the heart rate increases stroke volume decreases. You should remember that this is quite an artificial situation as this is solely looking at the effects of heart rate on stroke volume. Normally when we exercise this is associated with all sorts of other physiological processes (like changes in venous return and contractile force) which will tend to increase stroke volume but this will eventually be limited by this problem of inertia - there will come a point where the effect you see here will become limiting and cardiac output will fall. 6 Now, here's an interesting graph. This is life (on the X axis) and heart rate (on the Y axis). You can see that if you're a small animal (like a mouse) you live for about two years and you have a heart rate of about 600 bpm. If on the other hand you're a whale, or much larger animal, you have a heart rate of about 20 bpm and you live up to about 40 years of age. There is a very nice linear relationship between heart rate and life. Now if you're paying attention here you will realise that we bucked the trend. We have a resting heart rate of about 72 bpm and a life of over 80 years. So we are way off the line. So either we are a very weird animal or we have done something that has allowed us, through our changes in society and behaviour, to live a lot longer than we should do. If we extrapolate from this graph at 72 bpm, it predicts that we should live for about 20 to 25 years. That is, we should live long enough to reproduce at the age of about 13, then live to the point where our children are old enough to reproduce, and then we should die! We should die at about somewhere between 20 and 25 years of age. That should be our natural life if this graph is to be believed. When you think about it, in evolutionary time, what's the advantage of having a 7 grandparent?! Now you may say "Well, they can teach us all sorts of interesting things and we benefit from their experience". That is sort of true. It's may be true if you're a social animal (like a human). It becomes less true if you're a goldfish or indeed a zebra. These animals, when they get old, become a bit of a liability. They consume resources, they slow down the pack or the herd, they are ineffective in terms of fighting, or doing anything useful. So perhaps we are designed to live until our children are old enough to reproduce and after that we are surplus to requirements? I don't recommend you have this conversation with your grandparents, however, this seems to be like a sensible sort of evolutionary strategy. So if we accept that, then it's very clear that that period from when we're about 20 or 25 years of age to up to 80 (where we currently can expect to live) is a period where we're going suffer from chronic diseases as were never 'designed' to live this long. When you think about this appears to be true. That is, from about 25 years onwards we may get increasing incidence of diabetes, cardiovascular disease, cancer, chronic kidney disease, arthritis, dementia etc etc. These are diseases of old age. Ask yourself, does a zebra get chronic kidney failure or indeed cancer or cardiovascular disease? The answer is probably no! Because it gets eaten by a lion long before those chronic diseases take hold. So that grey area you see on the slide is actually an area that we were not designed to live long enough to experience! So chronic diseases are not something that our bodies have evolved to deal with. The way we deal with chronic diseases is very often inappropriate. We'll think about what that means in the context of therapeutics a little bit later in this lecture. While we're on this subject, the next slide shows an interesting consequence of these data - ‹#› This is the same data plotted in a different way. This time we've plotted the number of heartbeats in a lifetime (you can work this out on the back of an envelope if you like at some point). You can see pretty much every animal has pretty much the same number of heartbeats - about 3 x 108 heartbeats in a lifetime. You can burn them up all very quickly (if you're a mouse in two years at 600 beats a minute) or you can take life a little bit more slowly (like a whale) and you can live longer. But we all have about the same number of heartbeats in a lifetime. We've slightly bucked the trend. Our red dot (you see on this slide) is slightly to the right of the line - we get about 30 x 108 heartbeats in a lifetime. As I say you can work this out for yourself. There was a famously very large American cardiologist called John Morrow. He said "We were all born with a finite number of heartbeats I'm not going to waste mine on exercise". You can work out whether what he said is true or not? Let's just think about that for a minute........In other lectures you have heard that taking exercise actually lowers your resting heart rate. So if you're an extremely fit athlete (and have a heart rate of let's say 45 bpm), but you 8 achieve that by going to the gym for two hours every day to exercise maximally (with a heart rate of around 200 beats a minute), again you can work out on the back of an envelope....... does exercise cost you heart rates or indeed buy you heart beats? I should add at this point - don't get confused by these statistics. They are amusing but they relate much more to oxygen consumption and oxygen requirement than they do to actual life. If you want to think about the nature of longevity, one of the theories of what kills us ultimately is our inability to replicate our DNA effectively. Our DNA gets progressively more and more damage, our telomeres get shorter as we get older. Part of the stimulus for that appears to be oxidative stress causing free radical damage to DNA. We produce more free radicals if we have a higher metabolism and we produce less free radicals if we have a lower metabolism. So large animals, with a low metabolism, can have a lower heart rate - they need to deliver oxygen less effectively to the tissues. This lower metabolism has a knock-on effect that they get less DNA damage. Small animals, like mice, which have to maintain a very high metabolism to maintain their body temperature at 37oC. Particularly if they are living in the Arctic, for example, they need a very high metabolism. That high metabolism is going to have two consequences - 1. they need a high heart rate and 2. they're going to burn a lot of metabolic energy, produced a lot of free radicals and cause a lot of DNA damage. So don't get confused by the idea that lowering your heart rate may allow you to live longer. These two things are not causally related but they are interesting. I thought I'd mention them because it is an amusing thing to think about in the context of why we have the heart rate we have and indeed why we live as long as we do? ‹#› Although those previous slides in a range of animals were slightly misleading, as they reflect species differences in metabolic demand, it turns out that in people, heart rate is indeed inversely related to longevity. In this French study, you can see that if you subdivide a normal population according to resting heart rate, all cause mortality over 21 years is higher the higher the heart rate. This is in a normal healthy population. In the next few slides, we will think about how useful heart rate is in patients with cardiovascular disease. The specific patient population, or disease, is indicated in the inset in the top left of the slide. 9 10 In this very large study, called GISSI-3, the prognostic significance of heart rate was assessed in patients after their acute myocardial infarction. Multivariate analysis showed that heart rate had independent prognostic significance both in hospital and at 6-month follow-up. A strict relationship between increase in heart rate and 6- month mortality was evident in both patients taking and those not taking b-blockers. You can see here that if your resting heart rate is greater than 100 you have a 20% chance of dying in the year after your myocardial infarction. 10 11 This example shows that, even in hypertensive patients, the age-adjusted 2-year mortality rate from coronary heart disease (CHD), cardiovascular disease (CVD), and all causes is increased with increasing heart rate. As you can see here, the higher the heart rate, the worse the prognosis. There are many more studies like this, and the one in the previous slide, showing that a high heart rate is associated with a poor prognosis in patients with cardiovascular disease. 11 12 So, the important question is - is heart rate causally associated with mortality? That is - is heart rate a risk factor in patients with cardiovascular disease? As we mentioned earlier it could be that it simply a risk indicator that is the high heart rate simply reflects the severity of the underlying disease and an increase in stress and sympathetic tone. Lowering heart rate in this situation would have no therapeutic benefit. So, it's important to be able to distinguish between risk factors and risk indicators. 12 So here's a fact........people who carry matches are statistically more likely to get lung cancer. So the solution clearly is to give everyone a lighter. This is obviously a silly solution and shows that risk indicators are not always causal factors. To be a risk factor, something needs to meet a number of criteria – the most important of which is that when you lower it specifically, it needs to improve prognosis. In the next mini-lecture we will discuss the physiology of the SA node, how it’s regulated, and the pharmacology of heart rate modifying drugs. If you want to know more about clinical trials for heart rate lowering drugs, that’s the topic for a future lecture and we will not be covering it here! 13 14 Hello and welcome back to the second mini lecture in the series on the initiation of the heart beat. In this lecture we're going to describe the basic anatomy and Physiology of sinoatrial node cells and discuss how heart rate is controlled by pharmacological and neuronal regulation of nodal cell physiology. 15 We're going to start by discussing the pacemaker structures in the heart before concentrating on the primary pacemaker which is the sinoatrial node 16 It turns out there are a number of pacemaker tissues in the heart. This was first shown in a classical exoperiment by Hermann Stannius. He showed that there is, in fact, a hierarchy of pacemakers in a frog heart by tying a ligature between the sinus venosus and the atria. When he did this the heart rate slowed. He then tied a second ligature between the atria and the ventricle and showed a further slowing of heart rate. This experiment demonstrated that the primary pacemaker in the frog heart is in the sinus venosus but when that is isolated the atria contain a secondary slower pacemaker. There is a 3rd even slower pacemaker in the ventricle - driven by the Purkinje fibres within the ventricular muscle. There is a similar hierarchy of pacemaker structures in the mammalian heart. 17 The pacemaking structures of the mammalian heart are shown here in yellow and they are labelled. The basic properties of these pacemaker structures in the heart mean that the sinus node has the fastest intrinsic rate so it tends to be the conductor of the orchestra - it's the one that determines the rate of all the other structures within the heart. The impulse arises in the SA node and then spreads down these pacemaker structures from top to bottom. So although these other structures (marked in yellow on this diagram) have their own intrinsic rates, they're always marching in time to the beat that is generated by the sinus node. So it is the site the fastest rate and it determines the tempo of the heart. The next fastest structure in this pacemaker cascade is the atrioventricular node. The Bundle of Hiss also has an intrinsic frequency but this is even slower and finally the Purkinje fibres have the slowest intrinsic rate. Normally, when these structures are working properly, the conductor of the orchestra setting the rate is the sinus node and that is how it should normally work. If these structures start firing off at faster rates or at abnormal intervals then we have the generation of cardiac arrhythmias. Normally they all just march in time to the rate that is dictated by the sinus node. 18 So here you can see just an animated video of the impulse of arising in the right atrium. It spreads across towards the left atrium and it spreads down the septum and then radiates around through the ventricular wall. 19 So, as we have said, the primary pacemaker is the SA node. This is a small tear-drop shaped structure located at the top of the right atrium (top left hand side of most ‘front-on’ drawings of the heart). It lies at the junction of the superior and inferior vena cavae and is bounded on one side by a thick ridge of atrial muscle called the crista terminalis. You can see the superior and inferior vena cavae marked on this diagram as SVC and IVC and the crysta terminalis is shown by the dotted yellow line in the upper panel (marked CT). The sinus node itself contains a mixture of specialised nodal cells, atrial cells and connective tissue. This heterogeneous mixture of cell types is ESSENTIAL for the normal functioning of the pacemaker and changes to this structure when we get old contribute to aging-induced changes in heart rate. In the lower panel you can see a cross section of the node. One thing to note is that the node contains a lot of connective tissue, up to 50 to 90%, depending on species and age. 20 If we look in more detail we can see that cells from the centre of the SA node sometimes called 'P' cells are small, poorly differentiated, have very few mitochondria and numerous membrane invaginations called cavaeolae. They're essentially just empty bags of membrane. Towards the periphery of the node, the cells become larger and are better organised with more muscle filament's and a more well defined structure. For a number of years it was unclear whether these different types of cells formed discrete structures with a sharp interface between them, or whether there was simply a gradual transition from one cell type to another? It is now clear however that there is a fairly smooth and gradual transition from the centre to the periphery of the node. 21 In this slide you can see three different types of cells isolated from the sinoatrial node -what's called a spindle cell (from the centre of the node), an elongated spindle cell (probably from the periphery of the node) and what has been termed a spider cell. In all of these cell types you can see that there is a nucleus surrounded by a lot of membrane but very little cytoplasm. These cells have evolved to have the necessary structures to generate an action potential but not really to function as a muscle cell. On the right hand side of the slide you can see a more typical atrial muscle cell. Towards the periphery of the node the cells look increasingly like these atrial muscle cells with clear intracellular contents and well-defined muscle fibres. 22 This shows the characteristic action potential shape of SA node cells. The key feature is, of course, the region of ‘diastolic depolarisation’ (ie the sloping baseline between action potentials). This is also sometimes called the pacemaker depolarisation or phase 4 (IV) of the action potential. The pacemaker potential Is generated by a combination of inward currents increasing and outward currents decreasing. Once the membrane potential hits a threshold level sodium and/or calcium channels open generating the upstroke of the action potential. These sodium and calcium channels thenrapidly shut and potassium channels open repolarising the membrane back down to its minimum diastolic level. This process then repeats itself with a regular Clock-like a rhythm. 23 There are two theories about what generates this clock-like rhythm. These are called the ‘Membrane clock’ theory and the ‘Calcium clock’ theory. The membrane clock model says that the repetitive pacemaker is generated by ion channels in the membrane – this membrane clock theory is championed by an Italian researcher called Dario Difrancesco (who discovered something called the ‘Funny current’ while working in Oxford. We will talk about this current shortly. The Ca clock theory says that cyclical release of Ca from intracellular stores drives the membrane potential up and down in diastole and hence regulates the pacemaker. This model is championed by an American called Ed Lakatta and his co-worker Victor Matsev. So, in the Membrane Clock model the primary pacemaker is due to cyclical changes in ion channels within the membrane itself, while in the Ca clock model the pacemaker has its origins in cyclical intracellular calcium release which secondarily drives membrane potential changes. Both models are probably correct and influence each other! 24 A key player in the Membrane Clock Theory is called the funny current If originally described by Dario DiFrancesco. This current is an inward current - that is, it brings positive ions into the cell. Now, this particular inward current is very unusual because it is activated when the membrane potential becomes more negative - that is when the membrane hyperpolarises. This is really unusual because inward currents are normally activated by the membrane becoming more positive - for example in the upstroke of the action potential. Because of this unusual property DiFrancesco and colleagues in Oxford named this current the funny current or If. During the action potential this channel is closed. However when the membrane repolarises and becomes increasingly negative, this channel slowly opens bringing positive charges into the cell and hence the membrane potential turns around and gradually becomes more psotive. The membrane continues to depolarise until it reaches a threshold value where an action potential fires off. 25 The funny current then switches off as these channels become inactivated. There are a number of other ionic currents that switch on and off during this diastolic interval which also contribute to this pacemaker depolarization. In the Membrane Clock Theory it is the time-dependant and voltage-dependent activation of these ion currents that drives the repetitive pacemaker clock. ‹#› So which is it the membrane Clock or the calcium Clock? The answer is both are important and both can modulate each other both can be stimulated and inhibited by neurotransmitters such as noradrenaline and acetylcholine. Since the generation of an action potential is by definition a prerequisite for pacemaker activity it is clear that the Membrane Clock is likely to be the dominant mechanism but this can be fine-tuned by changes in intracellular calcium release and the behaviour of the Calcium Clock. 26 The next thing we're going to discuss is how the intrinsic clock function of sinoatrial nodal cells is regulated. 27 Sympathetic stimulation speeds up heart rate and parasympathetic stimulation slows down the heart rate. This slide shows the principle signalling pathways involved. Firstly, when acetylcholine binds to muscarinic receptors it directly activates a receptor operated K channel (called IK(ACh)) - this is a direct effect and does not involve an intracellular second messenger. Most of the neurohormonal regulation of heart rate, however, is mediated down-stream signalling pathways - the most important of which is via cAMP. While acetylcholine lowers cAMP, noradrenaline or adrenaline binding to beta receptors raise cAMP. Let's start by thinking about how the sympathetic nervous system increases heart rate. Raising cAMP exerts its effects in two ways. Firstly, elevated cAMP binds to the channel responsible for the funny current and increases this current. This is probably the primary mechanism by which beta stimulation raises heart rate. 28 Secondly cAMP activates Protein Kinase A which phosphorylates a range of targets including the L type calcium channel, phospholamban and the ryanodine receptor in the sarcoplasmic reticulum. The combined effect of phosphorylating these substrates and activating the funny current is to increase the rate of diastolic depolarization and increase heart rate. Parasympathetic nervous system activation involves acetal choline binding to muscarinic receptors which essentially do the opposite that is they lower the cyclic amp concentration in the cell as well as directly activating this receptor coupled potassium channel I ke AC H. Just to remind you the Membrane Clock is the dominant pacemaker mechanism but this is significantly regulated by the activity of the Calcium Clock and is hence influenced by the phosphorylation of the substrates within the sarcoplasmic reticulum. ‹#› Pharmacologically we can target different parts of this pacemaker mechanism. There are a number of drugs which will slow heart rate as part of the wide range of effects. These include drugs like beta blockers, L type calcium channel blockers, anaesthetic agents, anti arrhythmic drugs and even digoxin - which blocks the Na/K ATPase. All of these drugs have multiple other effects. There are only a limited number of specific bradycardic agents and only one of these ivabradine, is licenced for clinical use. Ivabradine is also known by the trade name Procoralan. 29 In this slide, you can see the effect of ivabradine on the funny current. The left panel shows the slowly activating funny current and how it is blocked by ivabradine. Don't forget inward currents are always plotted going downwards on the page. On the right hand side you can see how blocking this small current significantly slows the firing of the SA nodal action potential (and hence heart rate) by affecting the rate of Phase 4 depolarisation. If currents are also blocked by caesium (which is useful in the lab) but more importantly it can be reduced by the neurotransmitter acetylcholine. A range of pharmacological bradycardic agents have also been developed but, as I mentioned, only ivabradine has made it through into clinical use. 30 This slide shows the effect of I F blockade with ivabradine in a real clinical situation. This is what is called a forced-titration where the concentration of ivabradine is increased from 10 to 15 to 20 mg twice daily every week. Interestingly, in this slide you can see the effect we discussed earlier. That is you can block a very substantial proportion of the funny current and it does not stop the sinoatrial node completely. This is because, as we discussed earlier, there are multiple ion currents in the sinus node that provide a safe fail-safe mechanism. This is a very useful feature clinically as it alleviates fears about overdosing patients and causing cardiac arrest. 31 This slide shows you the molecular structure of the ion channel that carries the funny current. This channel is a member of a family of channel proteins called the hyperpolarization activated cyclic nucleotide gated cation channels - or HCN for short. Each HCN channel is made up of four subunits with each subunit containing 6 trans-membrane spanning regions. The transmembrane domain 4 contains the voltage-sensors that confer the voltage-gating properties of th channel. These 4 subunits go together like staves in a barrel to form the fully functional channel. The important thing to note is that each subunit contains a Cyclic Nucleotide Binding Domain on its C-terminal. 32 As we said earlier cAMP can be elevated in the cell in response to beta receptor stimulation and cAMP binds to this Cyclic Nucleotide Binding Domain and activates the funny current. Acetylcholine binding to muscarinic receptors lowers cyclic amp and inhibits the funny current. 33 This graph show what is known as the steady-state activation curve for If. HCN channels are voltage-dependent - that is they open and close in response to voltage. This graph shows how many channels are AVAILABLE for opening at each voltage. So, the more negative the cell membrane becomes the more channels that are able to be opened. The pink ‘stripe’ shows the voltage range of DIASTOLIC DEPOLARISATION in nodal cells (ie about -70 to -45 mV). Note: channel behaviour is actually more complex than this implies as channels also INACTIVATE - so the amount of current through a channel not only depends on the above curve but also on their INACTIVATION properties. 34 Beta receptor stimulation (with, for example, ISO (isoprenaline)) shifts the activation curve for HCN channels to the right. At -60mV this increases the available channels by 87% (as shown in the left panel by the red arrow). Conversely, acetylcholine (ACh) shifts the steady-state activation curve to the left reducing the available current (by 70% at -60mV) (as shown by the blue arrow). The net effect of this is shown in the right hand panel - ISO increases If and increases the steepness of the pacemaker depolarisation -hence increasing the the rate of firing of the node. ACh does the opposite. This steady state activation curve is also affected by thyroid hormones, other neurotransmitters, adenosine, nitric oxide etc. 35 Endogenously, of course, the most important regulator of heart rate is the autonomic nervous system. Classically we think of the sympathetic nervous system as being responsible for 'fight or flight' responses and the parasympathetic nervous system for 'rest and digest' responses. 36 Both the SA and AV nodes are richly innervated by neurons from both limbs of the autonomic nervous system. Sympathetic stimulation raises heart rate (and speeds conduction through the AV node) while parasympathetic stimulation (via the Vagus nerve) slows heart rate and slows AV conduction. 37 Heart rate is therefore under the influence of the sympathetic nervous system, applying an accelerator, whilst the parasympathetic system applies the brake. Interestingly, to extend this analogy, our heart 'drives along' with one foot slightly on the accelerator and 1 foot slightly on the brake. How do we know this? Well our normal resting heart rate is around 72 beats per minute. If we apply a beta blocking drug our heart rate will fall to less than 60 beats per minute - that tells us that normally there's a little bit of what we would call sympathetic tone. Conversely, if we inhibit the parasympathetic nervous system (with atropine or by cutting the vagus nerve as happens during heart transport the intrinsic heart rate increases to around 90 beats per minute. So this tells us that our heart at rest is normally under the control of both limbs of the autonomic nervous system. 38 So, given there are two opposing inputs controlling heart rate, how does this work in real life? This graph shows the heart rate changes over a period of gradually increasing exercise. The X axis is effectively exercise intensity (measured as oxygen consumption). You can see that, in the first initial phase when we start to exercise, our heart rate increases from a resting level up to about 90 beats a minute. Pretty much all of that change in heart rate is entirely mediated through the withdrawal of vagal tone (that is taking our 'foot off the brake'. So, when we walk up a flight of stairs, or just take a very small amount of exercise, our day to day moving around in the world, changes in heart rate are almost entirely mediated through alterations in vagal tone. If our heart rate slows down a little from 72 beats a minute or speeds up a little, as we move around the world, as we change our posture etc, almost all of that is mediated through changes in vagal tone. The same is true when we exercise. * When we start exercising, the increase in heart rate from around 72 beats a minute to around 90 beats a minute is pretty much entirely mediated by 39 'taking our foot off the brake' and withdrawing vagal tone and letting the heart rate speed up a little bit. * However, if you want to increase our heart rate further, during more severe exercise, we need to actually bring in sympathetic activation and circulating adrenaline, noradrenaline release from sympathetic nerve terminals and adrenaline released from our adrenal glands. ‹#› Before before we end this second mini lecture it is useful to define some terms frequently used when talking about heart rate. Often you will hear clinicians and scientists talk about the chronotropic state of the heart. You should be aware that 'chronotropic' means relating to 'heart rate' and a positively chronotropic agent increases heart rate and a negatively chronotropic agent decreases heart rate. 40 Finally whilst we're here, there’s a couple of more terms that we may as well define. We talked about chronotropy. You should also be familiar with these other terms. Inotropy is the strength of the contraction) while lusitropy is the rate of rrelaxation. Lusitropy is really important because it determines diastolic function in the heart (how quickly and effectively the heart relaxes in between beats). So a positive inotrope increases the strength of contraction while a positive lusitropic agent speed relaxation. So neeed to be with all of these terms. In the next mini lecture we will consider how once initiated, at whatever rate, the impulse spreads throughout the heart and how we can measure this on the body surface in the form of the ECG. 41 42 Hello and welcome back to the third mini lecture in the series on The Initiation of the heart beat. 43 In this final lecture we will consider how the wave of excitation spreads across the heart and basics of the ECG. 44 When the excitation arises at the sinoatrial node it spreads down towards the atrioventricular node being conducted through the muscle of the atrial wall itself. There are no specialised conducting pathways linking these two nodes. So conduction from the SA to the AV nodes is relatively slow. When the wave of excitation arrives at the AV node there is a pause. This pause is intrinsic to the properties of the AV node and it's there for a purpose. The first reason it's there is to allow the ventricles to fill before the wave of excitation is passed from the atria down to the ventricle. The mechanical filling of the ventricle takes a little bit of time and so there's a delay between the contraction of the atria and the required contraction of the ventricle. That delay is called the AV pause. This AV pause serves another very useful purpose. It stops really high rates of excitation being conducted down to the ventricles. We see that come into its own in pathological conditions like atrial fibrillation (AF). When the atria are beating far too fast as they do in the arrhythmia atrial fibrillation, if they passed on that very high heart rate to the ventricles the ventricles would not be able to pump properly - they would not have time to fill. So atrial fibrillation would become a lethal arrhythmia. Many people live quite happily not even knowing they are in atrial fibrillation. The reason they can do that is because the AV node filters out those high frequencies because 45 of the AV pause. This prevents those high heart rates being transmitted from the right atrium (from the SA node or from the abnormal atrial excitation) through to the ventricles. So there are two very useful reasons why there is this AV pause imposed by slow conduction through the AV. First is it allows time for the ventricles to fill before they are excited and contract and the 2nd is it prevents the transmission of high heart rates from the atria down to the ventricles. Once the AV node fires off, conduction through the ventricular conduction system is very fast and that spreads the excitation down the septum to the apex. This ad allows the muscle to contract at the apex essentially before any of the rest of the ventricle contracts. So it allows the sequence of contraction to start at the apex of the ventricle and push the blood up towards the outflow tracts (the aortic outflow in the left ventricle and the pulmonary artery in the right ventricle). By speeding that conduction very rapidly down to the apex of the heart we have an apex to base contraction in a nice sequence that mechanically works very well for ejecting blood out of the outflow tracts. ‹#› Once the excitation arrives at the muscle of the heart itself, it spreads from cell to cell along the leggth of the cardiac fibres. In this slide you can see a single cardic myocyte on the left and they are arranged like bricks in a wall making up the cardiac muscle fibres. At the ends of cells, the cells interdigitate to form tight junctions as you can see on the right hand side of this slide. These tight junctions are called intercalated disks and they facilitate electrical conduction along the length of cardiac fibres. 46 Intercalated disks contain protein channels (connexons) that span two adjacent cells (formed by hemi-channels within each cell). These are made up of proteins called connexins. They allow small molecules and electrical currents to pass easily from cell to cell. They go wrong in some pathologies like heart failure and this affects cell to cell conduction. 47 Connexons facilitate conduction along cardiac fibres. Conduction is less efficient across fibres. So, fibre orientation determines how conduction spreads through the heart. 48 In this slide you can see how complex the fibre orientation is and hence conduction is also complex. 49 Finally we're going to consider how that complex conduction across the heart can be detected at the surface of the body and so will review the basics of the ECG. 50 This is a picture of Augustus Waller. Augustus Waller worked at St Mary's Hospital in Paddington. He was the first person to record an ECG using the equipment that had relatively recently been developed. Here you see Waller in his laboratory on the left. You can see Jimmy his dog on the right hand side with his paws in little beakers of saline connected to some wires. The first recording of the ECG from Jimmy the dog is shown in the bottom left panel. You can see, interestingly, he's labelled the waves of the ECG he saw there to spell out the words BEST WISHES. This experiment was not without controversy and if you can actually read the details of this quite small print (right lower), here this is a report in the bottom right from Hansard (the Proceedings of the Houses of Parliament) where MPs had complained about Waller's experiments on Jimmy the dog. Complaining about use of animals and experimentation is nothing new! 51 51 Waller, having tested his ideas and his equipment on Jimmy the dog, moved onto measuring ECG's from people. He realised that clinically measurement of the ECG was going to be diagnostically useful. Here you can see a photograph of one of the early ECG machines used by Waller with a subject with their hands and a foot in buckets of saline to allow connection of wires to this instrumentation that you see on the left. The instrument that Waller was using is called an mercury electrometer and if you look at the top left hand side of the photograph you can see there's a tall column. That column contains mercury and that mercury moves up and down in response to changes in electrical potential. You could visualise that through the eyepiece on the right hand side of the apparatus or it could be recorded on a trace (as you see on the right hand side of my slide). Because this relies on a column of mercury moving up and down, it's quite sluggish. You can see that in the trace (shown in the slide) that it is quite sluggish - it's quite a slow wave and it doesn't really very faithfully reproduce the ECG as we know it today. That was the problem of using this mercury based electrometer type system. Present in one of Waller's lectures was a man called Willem Einthoven. Einthoven realised that he could build a much more sensitive type of equipment that a might that might allow him to get better resolution of the 52 52 ECG. ‹#› Here is Willem Einthoven shown in the photograph on the right hand side. Einthoven recorded an ECG that looks much more like the one you see on the left hand side. This is much more like the shape of the waveform with which you should be familiar Eindhoven did this by having a better recording device. He also realised a few other things -that is you need to have some sort of convention as to where you're going to record from on the surface of the body. As you've already seen from Wallace experiments, Waller used the arms and legs as a method for connecting to the torso. Einhoven said well this is a good idea but let's define which arms and which legs. So he defined what's called Einthpoven's Triangle. That is, a triangle that you see here which is made up of the right shoulder and left shoulder and the third Point of the triangle being the groin. We are all pretty much triangular-shaped so if we connect wires to our arms and legs then pretty much our arms and legs to connect to these three corners of the triangle. Einthoven reasoned that we can record from any of the 3 corners of this triangle and the heart is approximately at the centre of that triangle. So that will give us a convention. In other lectures you will learn more about Einthoven's Triangle, and the conventions we use for recording the ECG. The other thing Einthoven realised is that if we're going to record waves that go up and down, we need to give them some consistent names. So, he was the 53 first person, instead of writing best wishes under his ECG, he wrote PQRST. These letters became the now established names of the different waves within the conventional ECG. For his work, Willem Einthoven was awarded the Nobel Prize in Physiology and Medicine in 1924. He would have shared it with Augustus Waller but sadly Waller had died in 1922 and, as you probably know, Nobel Prizes are never awarded posthumously. So the Nobel Prize went solely to Einthoven despite Waller's earlier work. ‹#› You can think of the ECG as a wave of ‘postiveness’ spreading down the heart followed by a wave of ‘negativeness’. This is often referred to as the cardiac dipole. This dipole effectively moves along the long axis of the heart from the top (known as the base of the heart, towards the tip – known as the apex of the heart). Because of the position of the heart in the chest (more or less in the middle and pointing slightly to the left) this dipole effectively follows an imaginary line drawn from the right shoulder towards the top of the left leg. If we place a reference electrode on the right shoulder and a recording electrode on the top of the left leg, this should record the ‘dipole’ moving along this axis towards the recording electrode. 54 What does the ECG measure? If we put electrodes either side, or on any two corners of Einthoven's Triangle, we can put them so that they 'look' along one particular axis of the heart. Here I've shown a reference electrode at the top left (in blue) and, in the bottom right a recording or active electrode (in red). Those comnnections would be equivalent to the right shoulder in blue and the left leg in red. That's called Limb Lead I according to Einthoven's conventions. What would we record if we used those reference positions? The first thing we record is that wave of excitation arising in the sinoatrial node and spreading across the atria. That is the atrial depolarization. According to Einthoven's conventions he labelled that wave on the ECP - P. So this wave of excitation is a wave of positiveness spreading from the top left away from the reference electrode (in blue) and towards the recording electrode in red. So we get an upward deflection on the ECG which Einthoven named the P wave. 55 So what happens next is the wave of excitation moves down the Hiss Bundle and into the Right and Left Bundle Branches. Because those structures are relatively small, they don't make much tissue mass and so we don't see that spread of excitation on the ECG. What we do see is the muscle of the septum starts to depolarise a few milliseconds later. The first wave of depolarization comes from the middle of the septum - spreading up through the septal muscle back in the direction is has just come from. If you look at the diagram, you can see the arrow going away from the red recording electrode and towards the blue electrode. That gives us the little downward deflection on the ECG which we called the Q wave. Despite the fact that the excitation comes down the Bundle of Hiss, the muscle of the septum first starts to depolarise in a headward direction (towards the head). This headward direction gives us that little negative going Q wave that you can see on the ECG. 56 What then happens is the wave of excitation moves down towards the apex of the heart and that spreads through the muscle tissue and starts to depolarise the vast bulk of the ventricular muscle giving us the QR interval (the QR phase) of the ECG. This is due the depolarisation of the ventricles towards the apex from the middle of the septum. There's a lot of muscle here so that gives us a big upward going R wave. 57 The wave of excitation then turns around the tip of the apex and spreads back up through the free walls of the right and left ventricle's causing the wave of depolarization now to move away from our recording electrode. The wave then comes back down towards what we call the isoelectric line. It overshoots a little bit and we get what's called the S wave. So, so now we've gone PQRS and the whole of the ventricles have now depolarised 58 That depolarization persists for a few 100 milliseconds (~300-400 msec in humans) before a wave of repolarization brings a wave of negativeness spreading back up through the ventricle and that gives us the T wave or the repolarization of the ventricle. So here's all of the waves of the ECG identified according to Einthoven's convention. The P wave is atrial depolarization, the QRS complex is ventricular depolarization, and the T wave is ventricular repolarization. Note: you do not see atrial repolarisation as it is hidden by the QRS complex. 59 Here you can see, in a sequence of events, the ECG regenerating and the wave of excitation spreading down the heart through the ventricles, around up through the free walls, and giving us that PQRS and T pattern that now has become so familiar. So how do the different waves, and the timing of the different waves, relate to the action potential? 60 This next slide shows the ECG in the top trace (in blue) and a ventricular action potential and an atrial action potential shown below. The purpose of this slide is to show you how the timing of the waves of the ECG correlate with an atrial cell and a ventricular cell action potential. When the atria depolarise you can see the atrial action potential and, in the form of the P wave of the ECG, you can see the wave of depolarization spreading through the atria. When the ventricular action potential depolarises, that is coincident with the QRS complex of the ECG. The duration of the ventricular action potential is determined from the time of ventricular depolarization (the upstroke of the action potential) to the end of the action potential or the end of the T wave. This is called the QT interval. If you look at the diagram you can see two vertical red lines showing the QT interval. Now we don't see a wave of atrial repolarization (like we see a wave of ventricular repolarization). So why is that? Well, if you look at the duration of the atrial action potential (shown in grey), you can see that the atria tend to repolarise at about the same time as the ventricular cells are depolarising - so atrial repolarization is just lost - hidden by the much bigger QRS electrical signal that is coming from the ventricle. 61 The waves of the ECG tell us about the timing and spread of excitation through the heart from the sinus node through to the end of repolarization. The PQ interval tells us how fast the wave of excitation spreads from the sinus node to the firing off of the AV node. The PQ interval is therefore a measure of atrial conduction and the AV nodal delay (that I told you about earlier). So if we see a pathological change in the PQ interval (if it gets longer for example) that indictaes that we have a problem with the conduction of the wave of impulse from the sinus node through to the AV node. For example, AV block. If the impulse is not passing through the AV node properly, we can get what is called AV block. So the PQ interval tells us very useful things about how that conduction pathway is functioning. The QRS duration tells us how fast that wave of depolarization spreads from the top of the ventricle down through the ventricles, through all of the ventricular muscle. If the QRS duration is long, it means it is taking a long time for the wave of excitation to spread through the ventricle - so we have a problem with conduction down the Hiss Bundle and the Bundle Branches and through the ventricular muscle itself. The QRS duration tells us about ventricular conduction velocity. An example of where we would see a pathological change would be in Bundle Branch Block where the excitation is not moving through the specialist conduction tissue properly. This results in a long QRS duration. The ST segment of the ECG tells us about that phase where the ventricular action potential is depolarised. If you look at the ST segment, this is coincident with the plateau phase of the action potential. So the whole of the ventricle should be depolarised at this stage and it should stay that way for 300 or 400 milliseconds because of the long ventricular action potential. If part of the heart is damaged (such as ocurs during an evolving myocardial infarction or during ischaemia) then part of the ventricle may not be firing off an action potential as it should. So we may have areas of the ventricle which have a normal action potential and some areas of the ventricle that either have a very short action potential or no action potential at all. When this happens, the ST segment will change and we get what is called ST elevation (where this line on the ECG is higher than it should be) or we get ST depression (where the height of the ST segment is lower than it should be). So the ST segment is a very important indicator of myocardial ischaemia or an evolving myocardial infarction. If a patient comes into Accident and Emergency with a change in their ST segment of their ECG, this will ring alarm bells! Finally, the QT interval of the ECG. As we said earlier, this is a useful index of action potential duration/ Look at the dotted lines on the slide showing how the distance between the Q wave and the end of the T wave is approximately the same as the duration of the ventricular action potential. This is really useful because it's diagnostic of potentially lethal genetic channelopathies. These are mutations in ion channels (that people may be born with) that alter their action ‹#› potential duration and hence alter the QT interval. Long QT Syndrome is inherently very dangerous and so measuring the QT interval is diagnostically very useful. ‹#› So in this lecture we've reviewed the relationship between heart rate and body size in a variety of animals and we have reviewed the prognostic value of heart rate in life expectancy particularly in patients with cardiovascular disease. You should be able to understand the difference between heart rate as a risk indicator for prognosis and heart rate as a risk factor. * We've discussed the hierarchy of cardiac pacemakers and the cellular physiology of the primary pacemaker - the sinoatrial node. * We've described how the chronotropic state of the heart can be modulated by the autonomic input to the sinus node with the sympathetic nervous system accelerating heart rate and the parasympathetic nervous system, slowing heart rate via the vagus nerve. * We've described how heart rate can be modulated pharmacologically by the specific bradycardic agent ivabradine. You will learn more about the therapeutic use of this drug later in your course. * 62 We've described the cardiac conduction system and how excitation spreads through the heart from the SA node through to the ventricular muscle itself. * Finally, we've reviewed how you can measure that spread of excitation at the surface of the body using the ECG and we've described the physiological basis of the various waves of the ECG and why understanding these is clinically useful. Thank you for your attention. ‹#›