In this presentation, cardiac surgeon Dr. Michael Ibrahim, shares an overview of the concept his system is working on and why they’re devoting their time to this subject. Although there isn’t a large amount of new data, the story of heart failure has drastically changed over 50 years. New stories, outlines and information can be shown and implemented to a patient’s recovery.
@PennMDForum First of all, thank you for inviting me to speak and congratulations to Christian and Joyce and Audrey and Assad on a pretty wonderful symposium, I've learnt a lot and it's, it's uh a fantastic turnout. Um The gospel of Saint Matthew says that uh people who remain till the end will be saved and the people who got to the cellular mechanisms talk I think is, is who who the, the intended target of that statement was. So, thank you for sticking with me. Um uh My lab is here. Uh I don't have an acknowledgement line but I have the actual physical human being. So Carissa Basil Leo and Akeel and uh photos, they, the people really doing this work. So I thank you uh uh for that. My mission today is to give you a flavor of the overview of, of the sort of concept of what we're doing and why we're doing it. I'm not gonna share a whole lot of uh new data with you, but um uh here we go. So these are sort of some of my financial disclosures and uh but these are really my disclosures of my bias, which is probably more important. And so I believe that uh my recovery is common but ignored, undetected and unp promoted. There's an I CD code for a um uh AAA scalp injury by jet propeller, but no I CD code for coach recovery. Uh My card recovery will be much more common by the end of my career. Um And this will be driven by specific disruptive advances in fundamental knowledge of cellular mechanisms that underlie contraction, failure and recovery. And that's going to be mediated by gene therapies with mechanical unloading and possibly with cell therapy. Although I'm a little bit skeptical of cell of of cell therapy because it's substantially failed to deliver anything. Um The story of heart failure seen from a sort of broad perspective has changed dramatically. Over 50 years. We've gone from treatment with positive inotropes to negative inotropes, from veno dilators to ace inhibitors, from bed rest to exercise, changing uh exercise, train training. And the fundamental reason is this concept of remodeling that we're targeting and remodeling is a broad spectrum of changes at multiple levels, um both at the cellular and organ levels and systems and, you know, basically everything changes. So who knows uh what's important? Um But um you know, one particular uh way of thinking about it is that, you know, myocardial injuries lead to loss of myocardial function uh in terms of cell function and loss of myocardial cell number. Uh and both of those things uh ultimately to chronic overload of the surviving my. And uh you know, there are ways of treating that pharmacological agents and regeneration strategies that may try to increase cell number. But mechanical unloading has the sort of uh distinct uh effect of treating the underlying pathos pathos consequence, which is chronic overload of the surviving myocardium. Uh So, when we think about that, we're talking about really circulatory support and ventricular support. And in this context, we're really talking about mechanical and loading of the L V. Um And, and sort of means to recover that with uh both durable and temporary vs that we've heard about today. This is a typical uh patient, a 31 year old lady who had a peripartum cardy, uh had a crash and burn on uh on ECMO and then ultimately on uh a durable LVAD. She had a E F of about 10 to 15% and had a LVAD implanted as a bridge to recovery after 10 months of uh full support. Uh She had some complications and those complications um uh led to ultimately investigation of removal of the device. This is a ramp study which we don't need to go through. Um But basically she recovered and this is her function. How do I get this to play? So, uh you know, this is good L V function explanted durably. Um So it's possible it's real and this story of infection leading to investigation of, of, of recovery is really the uh the way that mechanical unloading induced recovery was discovered, it's a very old concept going back to the 1940s that some way of resting the heart could induce cardiac recovery. Um probably the best uh or, or most sort of impressive uh series is from Magda Aub in, in, in London, who was uh one of my mentors. And he showed that in a, a group of DC M patients with, you know, serious uh heart failure, DC M, 15 patients, 11 of them could be recovered with a targeted therapy. And these are real heart failure patients. If you look at them, their injection fraction was 12% they had, you know, dilated L V S. So it's possible, how is it possible? Well, uh you know, one of the ways is that looking for it and intending to use a device as a means for recovery, the first stages of terminating shock pharmacological agents to reverse a remodel. Uh the, the remodeling that we described and then inducing uh physiological hyper with uh other various means. One of them was uh beta two agonism with, but which I think has fallen out of favor. But um you know, basically targeted uh uh assessment and promotion of recovery and L VDs induce a substantial number of changes uh in multiple features uh both at the systems and organ level and cellular level. And they're driven by these three physiological effects. The first is improved forward flow. The second is unloading the left ventricle and then ultimately, uh and then they also improve coronary perfusion. So the the challenge is to understand which of these things is actually important. And so who cares about cellular mechanisms? Well, um if you care about contraction, which is really the currency of cardiac recovery, this is where it's happening. This is the cell membrane of a single myocyte. This is the the world of our lab. Um and you can see these imaginations of the cell membrane called transversal tubules. And these carry the membrane signal to contract and depolarize these red channels. L type calcium channels. And that voltage activation allows a small amount of calcium to enter the cell. And that a small amount of calcium, if it's close enough to this green channel, the rio receptor that channel which is activated by calcium by this calcium will open and allow calcium to be released into the mic into the uh uh cell and contraction will occur. These are the teaching bills. They are obviously very large and extensive and they're basically an evolutionary solution to the problem that cardiomyo sites are too big for the electrical current to sort of translate passively through the cell. Um So this the way to think of this is that this is a tap and this tap controls the degree of calcium that is released and therefore the degree of contraction. If you lose this tubule, if you dislodge this very close connection. Normally about 12 nanometers between these two channels. You will substantially reduce the efficiency of what we call calcium induced calcium release and therefore contraction. So, if you care about um contraction, which is our currency, then excitation contraction coupling is really at the very heart of the matter and doesn't get much more close to the mechanism than that. Um One of the ways that we discovered this is that this is a study from my group in, in, in, in London, my old group and they looked at people who had L A therapy, who recovered, who had explantation of the device versus people who who uh required a transplant. So that was our definition of recovery versus not recovery, pretty clear cut. And we looked at excitation contraction coupling parameters and found that, you know, uh one of the most important that the content of calcium in the sarcoplasm reticulum. This uh membrane here was significantly correlated with recovery versus non recovery. Um and also some other uh parameters to do with the al type calcium channel that led us to suspect that, that this tubule here, uh a loss of this tubule was important. Uh This evidence and other led to the C C A trial which is normally described as a neutral or negative trial. Uh I think that that probably is wrong. Um I think that probably that there are issues with the anti viral uh administration of circa in that trial. But where it was administered. Well, you can see there was a substantial improvement in survival uh in, in patients. Um So what are we really talking about here to, to kind of put this schematically, this T tubule here and this L type and CAL and, and random receptors are normally very, very tightly co localized and in heart failure, these T G bills are lost. And so what happens is that electrical excitation has to passively somehow reach this um this uh uh channel and release calcium. Uh And so what happens is if you look at the cell, this is a single cell that's getting scanned back and forth thousands of times when you stimulate it. In normal setting, you get a very rapid rise of calcium across the whole cell. In heart failure, it's patchy and delayed so that there are areas that the calcium is very, substantially delayed and those areas correspond to gaps in the T TB network. And we came up with the concept that maybe a mechanical unloading could induce reversal of these and recouping of these two channels. So to do that, we developed a heart failure animal model. Um and then a model of mechanical unloading using heterotopic heart transplantation in rats. And we basically showed that yes, in, in uh in heart failure, we see this classical uh disruption of the calcium release across the whole length of the cell. So this is an area that will have no tt bles where calcium is very much delayed compared to this, where you see normal setting, calcium substantially increases across the whole length of the cell. And mechanical unloading restores this basically to normal. Uh The second question is, well, is that due to T G bill loss and what we found was that T bills were substantially lost in heart failure and they were covered with mechanical unloading. Um And so, um this is some surface iron scanning uh showing the same thing and electronics showing massive dilation of these T G vs uh reduction in their number um that was restored by mechanical unloading. And then ultimately, we stained for these two channels, the diro up calcium channel, the same thing and the R receptor in normal in the normal situation, you can see that these very tightly colocalize in these bands in heart failure. This is totally disrupted and mechanical unloading was able to induce a really dramatic recouping rec collocal of these two channels driven by that uh improvement in um in T tubule density. And so we basically describe that that um if you take this chronically overloaded setting and you mechanically unload it, you can recoup and regenerate these T tubules and and therefore induce recovery of um of the cellular functions, contractile function. How does this happen? There are a lot of proteins that are um the one that we became interested in was uh a protein that we described called telethon, which is a novel stretch sensitive uh protein in the mammalian heart. And I won't um you know, go through all the details. But basically, we showed that uh that was a vital protein for uh the process of of mechanical and loading induced recovery. Um And so, um you know, we have some uh proteins that we think are involved. We have clear evidence that mechanical unloading induces reversal of heart failure. So, where are we? We're in the Death Valley of translational science. People describe it as this translational bridge, but the vast majority of animal studies have never been translated to uh to um to practice. And so why is that? Well, how do we build a bridge across that, that that death valley of translation? Well, one of the challenges we're using non human heart failure, we are using non relevant hemodynamic loading. Um We need direct human efficacy of of targeted gene therapy and human myocardium. We need direct mechanistic data that shows that it is that gene of action that is uh doing the work. We think it is and ultimately need to trial that in an LVAD patient. So, um we need a radically new experimental modality. And the challenge is that we've been using these single isolated cells in animals largely. Um And human myotomy is very hard to work with. If you try and isolate human cells from heart failure, you'll find that you get about 1 to 2% of cells that are alive and they last for a few hours. Um And so uh we have a, a revolution now in translational science in cardiovascular medicine, with the advent of a new technique called cardiac slicing. Codex slicing makes uh ultra thin uh uh slices of Myoor that has near 100% viability of human primary Myoor. It is totally uh multicellular intact, can be kept, kept alive at least for several days. And um uh you can set it up so that you can mechanically load it in a way that is very uh similar to the in vivo setting. And these are some of the papers that first described uh from my group in London. Um And, and this is a cardiac slice and you'll see uh just uh like, like doctor Spey was showing uh this is a 300 micrometer cardiac slice. It is basically a a heart in the dish. It has a vasculature, it has multi cell layers that could retain their cellular uh interactions. They are loaded on these sort of actuators and stimulators and can be kept in culture and they display all the um uh sort of typical features of of working heart. Um And moreover, they can actually be um subjected to specific hemodynamic parameters uh with a CV P A mean arterial resistance uh and other, you know, in vivo hemodynamic parameters and you can construct PV loops. Um you can also genetically transduce them and perform almost all single cell experimental techniques that, you know, normally had required um uh uh single isolated cells which are so hard to, to work with human beings. And so, um we have shown that uh you can induce typical features of uh pressure and volume overload in these slices by altering um uh the mechanical loading conditions by uh pre loading them, uh by altering their sarcomere length. And also by after loading them and varying the resistance against which they contract. Um And this induces classical uh volume and pressure overload, uh histological features. Um And uh uh uh also uh genetic features that are typical of uh volume and pressure overload. And so finally, we have a um a uh system that will allow us to use human myocardium to study it experimentally in the laboratory. Um And, and basically do a clinical trial in a dish. And so this is an L V core that will be subjected to vibrato slicing um and loaded uh with specific hemodynamic parameters, inducing mechanical unloading X vivo and using adeno vial transfection to target the of interest that we're interested in. Um And then to uh perform assays of the function and specific molecular mechanisms that we're interested in. And so this is our dream experiment that we're, that we're working on right now. Um And this is our general model that, that this uh teaching your system, which is so critically and fundamentally and directly related to contraction. Um is pathologically altered in heart failure but can be rescued by LVAD therapy by induction of specific molecular changes to stretch sensitive proteins um at the level of E C coupling. And so, my conclusion is that mechanical unloading is a potent promoter of L V recovery in selected populations. There are many mechanisms of which exci excitation contraction coupling is an important one and very direct and understanding the determinants of recovery is gonna lead to new targets both in the gene therapies, teachable therapies and promotion of uh new monitoring strategies for unloading induced recovery. Um And you know, ultimately L V recovery is possible, probably under de under promoted and hopefully we can change that.