Vadim Fedorov, Prof. of Physiology and Cell Biology at the Medical Center at Ohio State University, talks about a new way to better detect the precise point where arrhythmia starts to determine the cause of AFib in humans.
For starters, for our viewers who maybe have heard the term a-fib before, but they’re not really sure what’s going on, could you describe what’s happening in the heart when you have a-fib?
FEDOROV: Atrial fibrillation is the most common heart rate irregularity, electrical irregularities or cardiac arrhythmias. What does it mean? We all have our heart and we all have consistent electrical activation of our heart from primary area at the top part of our hard called sinoatrial node. Sinoatrial node is a main pacemaker of our heart which consistently generates spontaneous electrical waves and deliver these waves to the atria as well as to the ventricle, which is both part of our heart and main muscles. Just to remind you, we have four different chambers in our heart; at the top, right and left atria, at the bottom, right and left ventricle. Atria receiving the blood from the body or from the lungs, which is left atria, right atria, from the body and pumping in ventricle and left ventricle, pumping the blood already oxygenated through aorta to the whole body and right ventricle pumping the blood, still deoxygenated, which coming back from our body without oxygen, without glucose and directly to the lung when we get the oxygen. Every second of your life, you have consistent generation of these electrical activity. Our heart is never stopped. You might have a couple seconds slowing during sleep, but it’s maximum what we can see as a norm and only in the case when person is exercising too much. And sometimes, you know, the sportsman might have a slow heart rate. But if we do have additional energy source outside of sinoatrial node, which is located in the right atria, and that’s main group of the cell which consistently generating this electrical activity, we have another source of electrical abnormal activity which can counteract with normal and create very fast sometime electrical disturbance in our heart. Then what will happen, instead of regular contraction, atria first, then the left ventricle, and you can feel it, two different contraction, atria ventricle, atria ventricle, you have to live consistently with supply from the heart, our blood pumping and pumping. If the heart will stop in about 10, 15 second, person can lose consciousness. And eventually, if the heart stops in a few minutes, we will die. Heart will never stop in our life until the cardiac arrhythmia may happen. And this arrhythmia at the top part will create very fast and irregular heart rate, which is will not kill the person right away, but the atria instead of normal contraction will be wobbling, so like that. So the heart, they’re not pumping anymore, the blood to the ventricle. Even the ventricle will still have a functional contraction. But it would be not consistent. A few wave will come. The additional structure between top atria and ventricle, we call it AV node, is like electrical conductor of impulses between top part and the bottom part. And this electrical conductor can filter very fast activity at the top, but not all of them. As such the bottom part will beat in very irregular and sometimes pulse, sometimes very fast, and that person will feel the big changes between what I feel now. I hope you all feel now, right now, my heart can be fast or slow, but it’s OK. Our heart rate can change from 50 beats per minute, which roughly one time per second to, during exercise, three times per second, like 180 beats per minute. Three times in one second, and it’s fine when you do, like running. I do running so I may have that heart rate. But hear wobbling ventricle is not functional well. This person cannot do really exercise well, normal activity. But first of all, most dangerous thing will happen that the blood clot will form in this part of the atria because they’re not squeezing any more blood. And the area called appendages go with appendages both right and left, especially in the left, when this pocket is not squeezing blood anymore, and the blood clot can form in few hours only. And if it’s disconnected from the atria, it can go to the ventricle, go to aorta, and can go straight to the brain and block the blood supply to our brain, leading to stroke, meaning that atrial fibrillation is the most common risk factor for stroke. So if person getting a-fib and a clinician diagnosed atrial fibrillation, first of all, very often they have to prescribe blood thinners, make sure that decreasing their risk of stroke during dissipation. In many cases, atrial fibrillation could be misdiagnosed because not everyone can feel the big changes in the heart rate. There may still a little bit these irregularities because you may not feel the atrial contraction at all, you feel only ventricle big pump because what is the heart? Electromechanical pump. The electrical part primarily coming from the top atria and the mechanical main muscle function, like pump function, coming from the ventricle.
Is it possible for clinicians and doctors to be able to know right now precisely where the impulses are going wrong, where they’re going haywire to cause that a-fib? Or is it still guesswork? Are you able to map precisely right now or is that what you and your lab mates are working on, a more precise way of finding exactly what’s going -where the point of confusion in the heart is?
FEDOROV: Correct, correct. So during atrial fibrillation beginning, so we need to have, like I mentioned, the additional extra stimulus. And we call these triggers, which trigger this very fast electrical chaotic activity. But then after the trigger, we have extra beta. In both atria, we should look who is maintaining this electrical activity disturbance? And it’s not easy to find who is maintaining, and we call this substrate. It’s easier for clinicians to find the trigger, but the trigger may be in different locations. You found today I have in pulmonary vein, which is most commonplace for trigger and most common place where our doctor is targeting and finding them. But we have in different patients, different places. And if after, we kind of jumping between one or another one, I think, because oblation require additional explanation. But going back to the trigger and substrate, so and then somewhere in the heart, we have electrical tornado, which is generate this very fast electrical activity. And this tornado electrical, it’s not easy to find and very easily misdiagnosed because our atria have 3D complexity. It means not only the shape, but the difference between surface, external called epicardio and the inside of the cavity called endocardio. And the thickness will variable from half of millimeter to 10 millimeters, depends from where we are. At some point, the electrical activity of this little electrical tornado can happen inside of this wall. And you may not see them well from both AP or endo cardio, which only our clinicians have access. As such in clinical field, the clinician can see properly trigger but not substrate, which maintain it. And substrate is what we found. And it’s come from many of the clinical studies. It’s created by, first of all, tiny, small scars. We call this fibrosis. It’s remodel tissue induced by hypertension stretch of the atria, diabetes, obesity, obstructive sleep apnea and any additional cardiac disease can lead remodeling and tiny small scars happening both right and left atria. And when they form sufficient size substrate, that we call it specific arrhythmogenic now, because arrhythmia arrhythmogenic subtrate, which create like a hub, if you understand the word hub, like we have a station hub and from the station we get and deliver in different trains or like subways. And this hub is holding this most common electrical circuit which deliver through the different myocardial bundle here and there and different time electrical activity creates the house outside. It’s not always easy to find this hub and the clinical tools is only one surface tool. And you have electrodes, which I will show later, in our labs, which Dr. Hamel currently at this particular point, Dr. Hamel is the main clinical collaborator, a clinical electrophysiologist who is performing multi electrode method to define the electrical source and then destroy them. Because if you can find the source, we can have additional electrodes, which delivering, for example, a radio frequency high energy locally and just destroys this substrate, which maintains this electrical circuit disturbance. Do you understand?
I do. Why is it important to know exactly which point to ablate? I know you don’t want to do a lot of ablations, so why is it important for your colleagues in the clinic to know exactly where they need to hit with the laser?
FEDOROV: Thank you. It’s a wonderful question because that’s exactly where we going with all our studies. So conceptually as more you’re ablating, as more you’re destroying normal tissue, too. If you’re not targeted to only isomagnetic substrate, you can damage additionally atrial healthy tissue, but plus any ablation create additional scars in our heart is irreversible. Means they can be, if they aren’t targeted to the substrate, which already have scar, can create additional circuit and the electrical wave can go around now over the ablation scar. And there’s quite often side effect of ablation procedure when a patient may get treatment directly with the proper substrate, but plus multiple additional ablation, which is untargeted leading to additional atrial tachycardias, which require the patient have to come back. And doctors already have to treat atrial tachycardias created by previous ablation procedure. Or if you even miss the proper substrate, but still do this ablation outside of the classical pulmonary wing, which used for trigger, so millions of patient wasn’t treated properly. He will get or she will get again atrial fibrillation. And this case will be really hard to treat because you have not only natural substrate, but this ablation induced, which leading to more resilient arrhythmias, which may sometimes not possible agitated by this cardiac ablation procedure.
Can you tell me what you and your colleagues are doing here in the lab that are helping your colleagues in the clinic pinpoint? You talked to me a little bit about some machinery in there and some ways of actually finding a more precise way to map. Are you able to just describe that for me what you’re doing?
FEDOROV: Absolutely. Thank you. I’m happy to do it. So I moved here 10 years ago from Washington University in St. Louis. And when I’m looking for my new lab, for a new program, I’m always looking for the place where I can work directly with clinical electrophysiologists, clinical surgeons, specialists in imaging of the heart. My personal background, I have a Masters degree in physics and math, applied biomedical engineering, additional PhD in cardiovascular, cardiac electrophysiology of human heart. So combination of variety of my training allowed me to find different tools which we can apply to cardiac arrhythmias. The conceptual difference when I move here and establish great collaboration with our clinical electrophysiologist, Dr. John Hamel, Dr. (unintelligible), with our cardiac surgeons, transplant surgeons. We have great leadership here, Dr. Peter Muller, who is actually a vice president of research, the Ohio State University. I hope I properly cite his title. He has many titles. And with his support and our colleagues, Dr. Paul Johnson, we create that program, which we call Work Human Heart Program or the Human Heart Research Program. Why do we need the human heart is I’m a basic scientist, researcher, translational researcher, and we always study animal models, preclinical animal models, to develop new treatments. It could be cardiac ablation. It could be surgery. It could be medicine or new genetic approaches, which we also developing like IPS cells, stem cell research, everything with testing in animal models before it will come to patients, before it come to the actually from bench to bedside. But many animals have very different structure of the heart, cardiac anatomy, as well as molecular profile, genetic profile. The electrical activity may differ from us. So what we find in the human heart, we may never reproduce in animal models. Also, animals are usually healthy. We need to create, like, human specific disease in animals, which is not always easy to do. In the case of atrial fibrillation, atrial fibrillation usually develops in our late decades after the 40s, 50s and we come in 70s and 80s. So when we have up to 10 percent of people have atrial fibrillation. And conception right now in the United States, we have at least five million patients with atrial fibrillation. And I still think that about only 50 percent is having efficient treatment, and many of them not completely treated and still have a-fib at this moment. So we have to look on the human heart directly to develop more patient specific, human specific treatment. To get this human heart, we need to study them alive. So what we develop here already nine years ago at the Ohio State University, we have great collaboration with our transplant surgeons, and we can receive a live human heart donated from patients. When the patient will receive new heart, the disease heart with heart failure and usually advanced stages of heart failure, it also has quite often, about 30 to 40 percent of them have this cardiac arrhythmia too, because that actually could be one of the reasons why this person actually have heart failure now and needed a new heart. So we receiving the diseased heart with and without this history of atrial fibrillation right away from the operation room, put in the special ice cardiac solution which preserve the both function structure of the heart is the same solution used and which our doctors are using for donor hearts. Because if we have donor hearts, for example, in Cincinnati, it could be delivered here and the patient can receive the heart from Cincinnati, Cleveland, Chicago and Boston. Or it could be opposite situation when we can receive occasionally unused donor heart when a patient has a history of cardiac arrhythmia and unfortunately die in the car accident or because of the stroke and donate his organs for research, so many organs can be used -kidney, liver, lungs and saving up to 8 person, one per. You can save 8 person. So we always advertise donation, organ donation. We work directly with great organization here called Lifeline of Ohio. Its procurement organ -procurement organization coordinates all this transplant and organ donation. With their help, we are receiving also a live human heart but from donors, because this heart can be used for a new person or it could be used for research. But we can utilize this, a live heart, bringing the same type of, we do this transplant, we have two sources. A transplant heart very diseased, and donor heart -variety of disease, including sometime if a heart was damaged during a car accident. Even young, unfortunately, young 19-year-old kids, because they didn’t put their belt, the steering wheel brake in the ribs and punches the ventricle. This heart was healthy but cannot be used now for anyone. But we can use it.
So what do you do with the hearts, Dr. Fedorov? They’re in the preserved solution. You have a human heart. Can you describe for me what steps you take and what you look for?
FEDOROV: Absolutely. So after we bring hearts and in now we have on the second floor biosafety level lab, when we do dissection, and the heart used for many researchers here at the Ohio State, more than 25 different labs, faculties, both clinical, basic scientists, using the different part of the tissue. In our lab, we primary using the top part of the heart, which I describe, atria, both right and left atria, and we dissecting the heart below called AV which separate atria from ventricle but keeping that all preserved coronary arteries. In the ventricle study by I already mentioned many different labs, on the single cell level, gene level, on the tissue level, we bring in already in this room, on this table, still everything in the ice. The ice has very proper solution which keep the heart preserved and alive, it just doesn’t beat. Now, after this, we have to cannulate major two arteries, right and left coronary arteries, close all surgical dissected coronary arteries. As such, we can diffuse with the additional physiological solution, which have all ions, oxygen, and as well as we warm up the solution to our body temperature, 37. So it has the same electrolytes, glucose, oxygen as in our blood. After we prepare the atria here, make sure we clean all this leakage, it’s ready to be diffused, we reallocated atrias to another room, where we have physiological setup, we can hook to cannulas to the tubes and start the infusion and the normal pressure which we have on our body -this already warm physiological solution. And believe or not, but in few second, as soon the heart will be warming up, it will start beat again, because as I mentioned first, our atria has a specific group of the cells, which I mentioned, called sinoatrial node, the main pacemaker of the heart. This generates spontaneous activity, independent from your brain. You can’t tell your heart to stop, can you? Can you say, beat faster? You can do it only by doing something, right? Doing yoga, breathing, or exercise, but the beating heart would be in the dish. It’s maybe in a different reason, because if the heart has history of atrial fibrillation, it’s going to fibrillation straight away. And we have more ways heart without history, you will beat in sinos rhythm, which you currently have. And diseased heart -this history of atrial fibrillation, will go straight to atrial fibrillation. Now we have a real human heart in the live physiological condition called ex vivo -ex vivo -in vivo inside, ex vivo outside, but still alive. And they can keep the heart for up to 12 hours in this condition. Obviously, we have to use antibiotics. We have to use all the sterile tools, make sure we don’t have even contamination during this time. And the physiological condition up to eight hours, practically the same. Then it slowly starts deteriorate and that like 12 hours is kind of our limit for physiological status. But what we can do here using. We will have what our doctor still cannot do. We can apply new tools, 3-D imaging tools, very innovative thing, which allow us to see not only surface or from one on another side, electrical but electrical activation inside of the heart. We can visualize electrical activity behind this curtain, behind the curtain of our wall, and pinpoint directly who is driving this particular heart? Who is driving and how it’s driving and how many the sources? It may not be the one. It’s quite often, as more disease progress, is more is more substrate you might get, and it’s progression from one to up to 10. And when you have 10 different substrates, practically impossible to treat. As such, the whole point to treat earlier. Make sure the disease didn’t progress in the stage when even the hour we call it smart ablation procedure, which focusing on proper, like, targets and tools, already would be unfunctional because the atria will be remodeled so vigorously that’s practically it’s all one big scar.
How does what you’re doing and what you’re looking at inside and outside the heart in 3-D, how does that help your colleagues who are in the clinic? Can you make the bridge for me?
FEDOROV: Absolutely, absolutely. So we using the tool called near infrared optical mapping. Optical mapping means using cameras to visualize electrical activity. How we can visualize with cameras electrical activity? We need inject in our hearts specific fluorescent dye, which will sense electrical activity. And fluorescence there will be change once the electrical wave will propagate through the cells. All this cardiomyocytes, single cell, heart electrical beacon, tiny cells, we have about two million cells in our heart total. Less in the atria but enormous amount. They all have electrical activation, and this dye will stuck to the membrane and will have change fluorescent properties. It will be more or less when the electrical wave will propagate. So point is, if we using near infrared light, we’re moving away from the hemoglobin absorption rate. So if you remember, when you see the blood and you kind of leak blood or donate blood, it’s absolutely non-transparent for our visual eyes. But it’s transparent for infrared light, which we don’t see, but these photons, light can go through without distortion. Reason this near infrared dye which allow us to not only visualize in 3-D up to four eight millimeter into the depths. So we have electrical activity, literally scanning from AP to endo and visualize electrical activity the same way as if you’re familiar with jellyfish and some time, if you see jellyfish that has fluorescence, like glowing, we actually can see this glowing inside of the heart after we inject the dye. Well, this method, even we develop preclinical model, animal model, and we already tested this method, 3-D imaging in the blood perfuse preparation, and actually in animals right now, we can successfully see way more than any clinical electrodes can. But to help our doctors now, we utilizing exactly the same clinical electrode mapping tools what Dr. Hamel’s using at this moment. We can with optical mapping visualize where the driver, we call this isomagnetic substrate, or who is driving our atria, and they put electrodes, clinical electrode, at the top and compare. OK, now we know where proper target. How can this electrode see this? And if we’re moving electrodes away from the driver, what will be the difference? And from clinical standpoint, they don’t know who the really true driver is. We do. Now have this electrode mapping tool, mapping map, here there, the ground tools. And for that we have specific analysis of electrical signal, which helping for Dr. Hamel and your other clinical physiologist to define who is a true driver, who is false positive. Ablate, do not ablate. Applying more than an application with an artificial intelligence. So we are using machine learning. We educate artificial intelligence, computer tool, driver. Non-driver. Now electrodes will know who the driver is, who is non-driver, and because we using the human heart, not any animal models, and we using the human heart in true physiological condition, the same electrode as Dr. Hamel and that arrhythmia is the same atrial fibrillation. This information going directly to clinic now. And that’s one of the part our innovative research, which I’m going. Additionally, we utilize structural imaging tool. As I mentioned before, briefly, we have tiny scars in our heart. Tiny scars is fibrotic tissue. Fibrotic tissue. Orlando Simonetti, who is director of our research imaging.
If we can talk about the MRI because that is the next step.
FEDOROV: Correct. So after we finish with electrical mapping activity, which my map with fluorescence dye, 3D imaging with electrodes clinical, we also will scan our atria with high-resolution MRI, magnetic resonance imaging, using the contrast enhancement. And this contrast enhances specific scars in the atria or in the ventricle or cardiac scars. So in high resolution we can visualize these scars also in 3-D. Essentially we have functional imaging in 3D of the whole heart, electrical functional imaging, as well as structural image of this cars. And we marry them together, merging. And we see, yes, where we see this tornado electrical, which we also see specific scar morphology, like specific type of substrate, which we actually found this intramural mean between the wall. You may not see this from AP or endo, but it’s separate AP and endo. You have additional layer of an excitable tissue, remodal and excitable tissue, which electrically disassociate one side from another side in creating this electrical loop. And from one side, you’ll see is just exit. Place for exit. That is the same from another side, if you use an electrical electrode only. But using optical mapping we can visualize whole loop. This MRI already used in clinics. We’re working with Dr. Orlando Simonetti, who is the director of research, our clinical imaging research and specialist of MRI specialists. We study also the same approach in preclinical models, but as well as in our patients. We have small clinical trials ongoing when the patient will be scanned with MRI with contrast of the atria before ablation procedure, and we reconstruct the 3D patient specific atria and visualize with additional computational, using a lot of computational tools, the scars, and the scars helping Doctor Hamel already know where to look with his electrodes. So it’s additional tools already available and utilized. Plus, he already may have additional information how electrical tornado should looks if you’re using these electrodes. And electrodes could be different shapes, different amount of electrodes. But we all are testing them already in ex vivo heart. You have this information tool. Plus we have additional study which we recently published when we utilizing some pharmacological approach which allow enhance visualization of this tornado.
In your mind, the work that you and your colleagues are doing here in the lab are you helping save lives and improve quality of life for the patients that doctor Hamel and his colleagues are working with in the clinic? What you’re doing here with basic science and translational science, is that making an impact on the people that Dr. Hamel is seeing?
FEDOROV: I hope so. I truly believe it’s happening now, and what we do is our whole, our goal to do this research to saving people’s life as well as improve quality of lives. So by improving quality of lives, we allow many people have way more healthy another 10, 20, 50 years of the life. Any medication has side effects. Any treatment, even cardiac ablation treatment, has side effect like I mentioned. As more accurate we are, have that, we will be diagnosed and find this substrate, find this arrhythmogenic heart, make minimal ablation procedure only to the substrate, only to most, like, part which sustains essential fibration, as more house the atria will be. In addition, which I didn’t mention yet, but we have developed now in ex vivo human hearts another tool. So now we know we treat take this using ablation. But can we think in the future, can we, instead of destroying substrate, can remove this by using our cell approach, our genetic approach, so meaning rehealing this scar? So can we remove this scar? It was diseased tissue. Can we make this tissue healthy back? Can we remove this specific arrhythmogenic fibrosis? Because we do have fibroids everywhere. Our skin is fibrotic. We have many important part of fibrosis in our heart, which we don’t want to removed. And we found using ex vivo hearts and this absolutely noble thing, specific cells which make these bad fibrosis. So if we can treat these cells, we can prevent this developing fibrosis, can prevent this arrhythmogenic substrate, and this will be a new future direction in our team, not only using destruction of this source arrhythmogenic heart, but using the healing of the heart and removing the arrhythmogenic fibrosis in a different way.
Interview conducted by Ivanhoe Broadcast News.
END OF INTERVIEW
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