Welcome, everybody, to Physiology of Hiss Bundle Pacing. Byron and I were just chatting about the number of people that have shown up to this course. And I was telling Byron that the first time I did a Hiss Bundle was 2006. I presented a live case that was pre-videotaped in 2008 at Heart Rhythm. And there was, you know, you could hear a pin drop at that presentation. So, you know, it's really amazing the talent that has come to the fore in really amplifying the message that this is something that we should all be paying close attention to has been really astoundingly impressive. And I think we're going to see some of that in today's session. The first speaker is going to be Sanjeev Saxena, who is going to tell us and teach us about Physiology of Hiss Bundle Pacing. Good afternoon, Mr. Chairpersons. I am particularly delighted that this session is taking place because there is a particular interest I have had in this area due to the fact that my mentors were pioneers in this space. And I will point out some of that. Earlier today we honored Tino Castellanos for his work, and some of it was in this space. And now I'm going to mention some other things, and we have the distinct privilege of one of them to be here. Now I'm going to talk a little differently than perhaps you might think the topic warrants, because I'm pretty sure that those who speak after me are going to show you clinical electrophysiologic tracings based ECGs, a variety of clinical information around his bundle pacing. I'm going to visit an area that perhaps is being overlooked for a little bit, and that is to turn back to the experimental concepts that are relevant to the clinical technique. What is the anatomy relevant to his bundle pacing physiology? What's the physiologic and pathologic propagation in the his bundle and the Purkinje system? What about ventricular activation patterns in normal and diseased his bundle? Subsequent to electrical activation, there is ventricular systolic contraction, and is it coordinated? What's the reserve in the his bundle for coordinated ventricular contraction? And what about the concept of his bundle disease and incoordinated ventricular contraction? These are areas that we need to look at by individual aspects and in detail, and I don't have time in 15 minutes to go over this in great detail with you, but I will touch on many aspects of this to stimulate you to think about it, delve into it, and come back to us in future times to tell us more about it. The classical concepts of his bundle and Purkinje system anatomy are owed to these three individuals, Purkinje, Tawara, and Koch, and Koch and Tawara were in the same laboratory. This is a classic anatomy drawing that you've all seen, but it led to the concept of main branches of the bundle of his and sort of a central system with propagating out into the two ventricles and eventually the trifascicular concept put forward by Rosenbaum. This is a work by the postdoc student of Henri Colbertus, Dr. de Moulin, and in this work, for the first time, he made some observations in these dissections suggesting that there was some interconnection, fairly proximally, in some patients among the main branches. Now, why does this relate to what we talk about today, and I'll come to that a little later. Now, what we talk about today currently in his bundle basing is sort of derived from this classic figure from a paper by Omkar Narula showing this lesion in the bundle of his, pacing proximal distal to this lesion, the ability to demonstrate normal QRS, appearing QRS complexes in the patient left bundle branch block, suggesting that there were predestined longitudinally dissociated fibers in the main bundle that were activated and then eliminated the electrical delay in the left bundle branch. And this concept he reinforced by showing an atrial premature beat, which is a more proximal pacing mode, not changing the bundle branch block. Now, this was a nice concept to have, but I would try to explore this to suggest that you need to think more and beyond this whole issue. So this is an anatomic study from Romero and his colleagues, showing that there are longitudinal connections between cell in the cellular architecture, just as you would think in terms of longitudinal preferential propagation, but there are also a lot of transverse connections between these cells at multiple levels. And you can see that in this detailed high magnification photomicrograph. And if you look further at immunostaining for connections, this is taken from Penny Boyden, who published this paper just last year, shows that connection 40 and 43, a distribution here, and they overlap in this moisture in what appears to be the intercalated disc regions at the possibility of transverse conduction in these people. Now, this is taken from Bob Meyerberg's postdoc dissertation, and we have the pleasure of having him here today. And Bob did this in Brian Hoffman's lab. They had a bundle branch preparation with isolated myocardial tissue with it and looked at a variety of stimulation strengths for propagation for the Purkinje fibers as well as myocardial potentials. And what you can see at high stimulus strengths, you get activation of both virtually simultaneously. If you reduce stimulus strength here, it's 1.2 times threshold. You only get preferential Hispokinje activation, no myocardial activation, subthreshold that is not. And then here is, of course, direct septal stimulation. Mapping this activation, which he did with Henry Gelband in this seminal work, showed that as activation along the bundle branches, and if you look at the myocardial potentials, they're activated in reverse, showing that you come out of the system and go back up through this. Now, if you look at the left bundle branch, there are similar observations. And you can see this coming through the left bundle branch. Here's the myocardium. That's the high septum, which is activated last. Now, what happens when you get lesions in this? I'm going to just focus on the last two here. Here's a horizontal incision to a main trunk of a bundle branch. And there is minimal delay compared to the baseline state. A vertical incision also did not produce great delay. But once you had both incisions, you suddenly saw remarkable delay. Now, to me, it makes the point that you need a certain and significant amount of conduction interference by disease to get to see these kinds of delays that you see in the left bundle branch block. Now, the issue of transverse conduction also was put forward and was looked at around the same time. This is a seminal paper by Ralph Lozada, who is not with us anymore. And to summarize it, here are recordings across the main bundle of hairs showing that there is simultaneous activation of positions A, B, and C. There's transverse propagation. And Bob also did studies exactly at the same time, suggesting that this longitudinal delay around the lesion only extended for a millimeter or two. And then transverse propagation appeared. In addition, the propagation characteristics along the course of the bundle branch were not uniform. There were areas of more prolonged activation, action potential durations, which we can refer to as a distal gate. And these had longer functional refractive periods and could slow down propagation. In fact, you could get, at certain pacing cycle lengths, higher degrees of block in the distal Hispokinji system. Now, how does that relate to what we talk about? It is the issue of disease and what it does to different regions of the bundle branch block, and what do we see in humans. Now, this is the kind of thing we see all in our clinical recordings. I'm sure there will be other speakers who are going to talk in detail about this. I'm only going to talk from the conceptual point of view. Here's a diseased area on a supposedly preferentially directed, longitudinally directed fiber in this image. And here's a stimulation that's being done that manages to capture these results in propagation of the bundle branch and gets rid of the delayed conduction. Now, is that really what happens? I think that we need to talk further about that. Here's another rendition from Mark Esty's group showing pacing proximal to the area of disease, at the area of disease, left and right of the area of disease, and what does this mean when we know what we know about transverse conduction in the bundle of His. And this phenomenon, and this is a case report from Vijay Raman, which did unipolar and bipolar pacing in the left bundle itself, again showing similar phenomena of the kind we've seen earlier at different voltages capturing varying degree right and left ventricle myocardium and then only the isolated bundle, and ending up with a variety of QRS patterns, and I'm sure they'll be discussed later. Now, let's turn to the thing we care about on the mechanical side, which is what about coordinate ventricle contraction, this 3D electroanatomic map of intrinsic sinus rhythm. Here's biventricular pacing, and you can see that biventricular pacing clearly advances ventricular activation in the left ventricle, but there are still areas of conduction delay in both ventricles. Selective hisponal pacing seems to smooth this out, and nonselective hisponal pacing pre-excites areas of myocardium in the right ventricle in this case. So this is a little quoted paper, but I think this is an important paper, which was published by Giuseppe Vergara's group, looking at the basic interventricular conduction delay measurements that we look at, septal posterior wall delay, and its behavior in what's normal, what's abnormal, and this is a comparison between right ventricular apical pacing, hisponal pacing, and hisponal plus septal pacing, or nonselective pacing, and in these indices, his interventricular septal delay on the echocardiogram, septal posterior wall delay, both selective and nonselective pacing were superior to right ventricular apical delay. These tracings are taken from one of Luigi Padaletti's last papers. We lost Dr. Padaletti last year, and in this paper, he did acute pressure volume loops studies in humans with different forms of pacing, and the pressure volume loops with hisponal pacing, showing here in blue, were comparable to LV only, or bi-V pacing, and superior to atrial pacing with left monobranch block. You can see this color coded here. Here's atrial pacing with monobranch block in black. There's hisponal pacing in blue, LV pacing in red, bi-V pacing in white. Now, they sought out optimal AV delays to get the best results for stroke volume, stroke work, and DBDT, and what they found was that, first of all, they could get optimal measurements for both forms of bi-ventricular LV pacing, and they found an optimal AV, and hisponal pacing compared, but hisponal pacing maintained some degree of that benefit, even at AV intervals that were not optimal and was not so sensitive to AV intervals as bi-ventricular and LV pacing was. In the search for getting better response to pacing modes in heart failure, we've been looking in more detail at activation patterns and contraction patterns in both CRT responders and CRT non-responders, and this is sort of a classic concept that suggests that if you have the septal flash that is present, these people often have good CRT response. In the absence of this, this is not the case, and the question then arises, are these patients particularly aware we could get something with other forms of pacing? So I'm going to conclude this talk by leaving you with some thoughts that I think the next talks will build on the clinical part of this, that the anatomic physiologic concepts need to be revisited in the modern era. The original concepts of longitudinal dissociation of hisponal conduction are now evolved further. Hisperkinesis system propagation in normals has unique and segmental and regional physiologic characteristics that we need to know more about. Gross and microscopic anatomic detail reveals a macroscopic syncytial network at the level of the primary bifurcation of the bundle branches, as well as peripheral arborization to provide substantial redundancy in propagation. And cellular and subcellular architecture further enhances EP reserve by permitting transverse propagation in the main bundle and its branches. Clinical hisponal and bundle branch disease most probably reflects very extensive disease in the HBS. Hisponal pacing leverages this complex physiology to reengage the remaining propagation pathways, and ECG patterns and mechanical resynchronization results from these features of the hisperkinesis system. So I'd like to conclude by saying this morning I had the pleasure of having one of the pioneers in hisperkinesia physiology, Dr. Tino Castellanos, and today Dr. Meyerberg is in our audience. You may never think that I was ever a student, but I was, and it is a pleasure as a student to honor a mentor. Thank you very much. applause

Hiss Bundle Pacing

physiology

anatomy

ventricular activation

clinical outcomes