Dr. Stavrakis is a clinical electrophysiologist and physician-scientist at the University of Oklahoma Health Science Center. He has been researching noninvasive autonomic neuromodulation for the last 10 years to treat atrial fibrillation and heart failure. Listen in as he explains the connection between our heart and our nervous system and shares a simple device which may redefine treatment for atrial fibrillation.
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AFib Treatment Breakthrough: A Noninvasive Approach With Dr. Stavros Stavrakis
Welcome to another episode. This one is going to be a mind-blowing experience. I’ve got Dr. Stavros Stavrakis and he’s here to enlighten us on some cool technology. Also, he is talking about the dynamics of how the brain and the autonomic nervous system impact cardiovascular health and wellness. As always, I’ve got Dr. Lauren Lattanza here, a naturopathic medical doctor at Natural Heart Doctor and I will let her do the intro, but first, let me say hello to you, Dr. Stavrakis. It’s great to see you.
It’s great to see you too, Dr. Wolfson and Dr. Lattanza. It’s my pleasure to be here and share my experiences with you and with your audience.
Dr. Lauren, take it away.
We’ve got a great guest for you. I’m so glad you’re here, Dr. Stavrakis. Dr. Stavrakis is a Clinical Electrophysiologist and Physician Scientist at the University of Oklahoma Health Sciences Center. He is an Associate Professor of Medicine and the Director of Cardiovascular Research. He has been routinely performing complex ablations for many years. His research has focused on autonomic neuromodulation for the treatment of atrial fibrillation and heart failure in both animal models and in humans.
His work culminated in a first-in-human randomized clinical trial, examining the chronic effect of noninvasive vagus nerve stimulation in patients with paroxysmal atrial fibrillation, which was presented as a late-breaking trial at the Heart Rhythm Society scientific sessions in May 2019. His goal is to continue to explore the role of the autonomic nervous system in cardiac arrhythmias and provide his expertise in both clinical procedures and research activities. It is huge and tremendous work. We have a lot to learn from you here.
Thank you very much. It’s my pleasure to share my experience.
Let’s roll right into it. First and foremost, what led you to become a cardiologist?
I was fascinated by the complex physiology of the heart and I had a great influence by my mentor, Dr. Ralph Lazzara, who unfortunately passed away, but inspired me to become a cardiologist like him.
How within that did you develop an interest in atrial fibrillation and the autonomic nervous system?
We could do better if we can study each patient individually. Unfortunately, we don’t have a good way to study the mechanism of AFib in the individual patient.
I trained at the University of Oklahoma and there was tremendous work in the field on autonomic influence on the heart. Ralph Lazzara and Ben Scherlag were pioneers in this work. I had them as mentors and I got led into this exciting field.
Let me take it from there and ask you. Can you give us the 101 of the autonomic nervous system, like the brain and heart connection as you see it?
The brain controls the heart function and the heart gives multiple messages to the brain, so it’s an interactive relationship. One influences the other to fine-tune the heart functions beat by beat.
As we look at the autonomics, we talk about the sympathetic and parasympathetic nervous systems as part of that. Everybody, they’re all in this sympathetic overdrive. It’s this sympathetic tone. We’re all under stress. We are all angry and depressed. We are all in this fight or flight mode. If the autonomic imbalance or again, this high sympathetic tone and underactive parasympathetic tone, how would you say that plays into AFib?
A-fib is unique in the sense that you need both ingredients. You need both sympathetic and parasympathetic to make AFib. Other conditions like heart failure are characterized by a heightened sympathetic tone and diminished parasympathetic. This has been shown for AFib in both animal and clinical studies. Before the onset of AFib, there is a search of both sympathetic and parasympathetic tone. We’ve shown in the lab that if you mix the two together, you’re more likely to get AFib versus one or the other alone.
It’s this whole autonomic surge.
You’re right. It’s different from heart failure. In heart failure and other conditions, even diabetes, there is a constantly elevated sympathetic tone, but with AFib, you may be in the normal state with balance and then for some reason, you get an imbalance. Like for people with Vagal AF, you eat a big meal and there is a high vagal tone and a little bit high sympathetic tone. You get a surge of both and that’s it. You get AFib.
Is there a percentage you could label on people? What percent of people are maybe more of that parasympathetic-driven AFib? As you said, they get it after a meal, after a bowel movement, after urinating or maybe they suffer from nocturnal AFib. They wake up in the middle of the night and they go into it. Percentages of parasympathetic versus sympathetic or a combination?
I would say the majority is a combination. Vagal is about 10 to 15%. Sympathetic, where they get it with peak exercise is another 10 to 15%.
Are there certain pharmaceuticals that you find benefit the parasympathetic version? Those people that do it happen after a bomb movement, after a meal, or awakens them up for sleep, should we be considering different pharmaceuticals for those people?
It hasn’t been specifically studied for those people. Unfortunately, we use the one size fits all approach because of the kind of knowledge. We could do better if we were able to study in each patient their specific mechanism, but we use antiarrhythmics. We use flecainide, propafenone, sotalol, amiodarone, you name it. We use them with respect to the mechanism, which is wrong, but we don’t have a good way to study the mechanism of AFib in the individual patient.
In my experience and in my training, we talked about those people with what appeared to be vagally-driven AFib based on their symptoms and the story that went along with it. We would use the old Norpace or disopyramide because of its vagolytic effects, but again, I think that may be more theoretical and may not have much evidence behind it. Would you agree?
Yeah. It’s not used anymore. Plus, it produces QT prolongation, so we went away from that.
What do you have, Dr. Lauren?
What led you to study the Parasym device?
I would call it serendipity. We did a proof of concept study with a custom-made tragus stimulation device. We showed that in people who came to the EP lab to have AFib ablation when we stimulated their tragus with our custom-made device that was something like an alligator clip. The AFib duration was significantly reduced after one hour of stimulation, and that was before any ablation was done. It was during the preparation time.
At that time, we were looking to expand this study to ambulatory patients with AFib. I got an email from this company in Finland who were developing this device to treat tinnitus. They said, “We’re trying to expand. Are you interested in testing our device in your AFib population?” I said, “That’s great. Of course.” That’s how it started. We tested the Parasym device in our clinical trial, which you alluded to, and it was the first-in-human randomized clinical trial of noninvasive vagus stimulation for AFib.
What results did you find?
We found that the median AFib burden was reduced by 75% at six months in the overall population. The AFib burden is the percentage of time people spent in AFib during the two-week monitoring time. We didn’t monitor continuously. That’s one of the caveats of the study. We could have seen larger effects had we monitored continuously.
That’s very impressive. That’s better than pharmaceuticals. That’s better numbers than ablation. I know all the ablators like to think that they’re the best in business and they’ve got super high success rates, but most of the data, at least that I’ve seen, it’s 50% success. Maybe you can dive a little bit deeper into some of those numbers.
To clarify a few things, the 50% you mentioned is AFib versus no AFib, so 50% will have no effect. Our metric was a little bit different. It was a non-traditional metric. It was AFib burden. The AFib burden is becoming more and more our traditional metric, but the common metric of AFib procedural success rate is sinus rhythm maintenance or a percentage of people with no AFib at all. That’s where the 50% comes in. In our population, we had a 75% decrease in the median AFib burden.
Where were you surprised by those numbers? Were you surprised by the success or do you think that some of the preliminary work that you had been doing prior to that showed you that this is likely going to be the results?
Yes, the latter. We were expecting to see something of this result. The magnitude surprised us a little bit but in a good way.
You publish this data and now it’s like, “Here’s Dr. Stavrakis and he’s on CNN, he’s on Fox, and he’s the keynote speaker at the American College of Cardiology meetings,” because this is incredible stuff.
True, but as you alluded to, we’re going against the mainstream. We are advocating an alternative treatment which doesn’t cost a lot. It doesn’t make money for the hospitals, so there is some resistance to uptake it.
I’m not sure that I alluded to that, but since you put it out there, people who know me, I would certainly be in agreement. Give me a little more detail on this. Why can’t our patients not get the Parasym in the United States?
I will say that to our surprise, there was a bi-modal response in the patient population we studied. Half of the patients responded very well with almost complete elimination of their AFib over six months, and the other half did not respond. Some of the skepticism of the cardiology community would come from this caveat. We don’t know who’s going to respond and who’s not.
I think we need better patient selection and a biomarker of response. That’s one thing. Now, why the Parasym is not available in the US, depends on the company. It’s a small company. They pursued approval, but the FDA needs more data, so we are in the process of designing the follow-up study, which would have more patients. It will be a multicenter study and up to FDA standards.
Before I go back to some of the things that we said there, what is the downside of the Parasym? What is the downside of that low-level tragus stimulation that you said? Were there any signals or any kind of risk that you saw in your study?
We didn’t see any risks related to the device. By FDA designation, it is a non-significant risk device. What I tell my patients is that the worst-case scenario is not going to work, but there’s not any harm in trying it.
I’m going to make a statement and then you can agree or not agree. I think you did allude to that before. The way I see it is that the FDA is not approving this device because it works so well it may decrease the number of ablations that people go through. It may decrease the number of pharmaceuticals, of course, that is used.
As you said, it is a cost-effective and no-risk technology, but in a world of conspiracy theories that the pharmaceutical companies, all the electrophysiologists and all the device companies are all predicated on the cardiovascular AFib treatment model. They are conspiring against doctors like you and this cutting-edge technology and it’s a very sad situation.
I think that’s an extreme statement. I won’t agree 100% with that. To clarify, what the FDA said was that metric we used, the AFib burden is not the standard one. I think subconsciously, electrophysiologists would prefer to be doing ablations and not compete against something else because now, with the current evidence, ablation is the best treatment for AFib and I say that with full honesty and looking at the data. I don’t have any personal bias. This is the truth. This is the data we have now. The ablation is the most successful therapy for AFib.
How I view autonomic modulation is an alternative approach. I don’t think we should look at it as competing because AFib is a progressive disease. You may do your Parasym or autonomic modulation because you can use other devices as well, and at some point, it may not be effective. There are a lot of things we don’t know. We did a six-month study. What’s the effect in two years? We don’t know.
Are there other centers that are interested in this technology and in collaborating with you on papers and research? I say plenty of things that are outside of the mainstream and I’m certainly not going to hold you to that. You’re as an expert talking about autonomics, the Parasym and about your study, and that’s all anybody should take from this.
My theories are my theories, but again, how do we get more people? Your study was so compelling and also makes fundamental common sense about how if we address the autonomics and autonomics dysfunction, automatic autonomic insufficiency, and if we improve on that through a variety of mechanisms, and that can be dietary, lifestyle and it could be device-based therapies as far as getting collaborators on pushing this forward.
We have an established collaboration with UCLA. We published a study together on the role of a neuropeptide Y as a biomarker for patient selection for response to autonomic modulation. We also have collaboration with MGH in Boston. I know Duke is very interested as well and Indiana University, to name a few. Those centers that have a tradition in starting autonomics, they’re very interested in this technology and in this concept.
Before I let Dr. Lattanza ask a few more questions, let me ask you as an aside. This is a total side break here. Does the fact that you are originally from Greece and your native language is Greek, how much advantage did that give you in medical school? All of the terminology and all of the roots of medical terms come from the Greek language. Was that like cheating? What do you think?
Yeah. In a way, it’s cheating. There’s a big advantage. I would say 50% of the words are purely Greek. We’re talking about dynamic, the term dynamic or sympathetic. Why do we do a right sympathetic with a Y? The Greek is with Epsilon, which is the equivalent.
What about the word dysfunctional? Is that also that’s coming from Greek?
Part of it. Whenever you say DYS, in Greek, that means something bad. The function comes from Latin. There are a lot of words that are mixed. The first part is Greek and the second part is Latin.
Didn’t the Latins steal it from the Greeks anyways?
Sometimes, but not all of the words, we have to give them some credit. If you know both Greek and Latin, you can fly through medical school.
Future med students, add that to your list of prereqs. Pick up Greek and Latin.
I knew neither. They talk about as people travel around the world, what do you call someone who speaks many languages? Multilingual. What do you call somebody who speaks two languages? Bilingual. What do you call someone who speaks one language? American. Lauren, tell me, what have you got?
We hit on this, but maybe if and when Parasym will be available in the US and are there other devices besides Parasym that might be hitting the market if they’re not already there?
I’ll answer the second one. There are a lot of devices for transcutaneous vagus stimulation. There is a device called gammaCore, which you have to hold your vagus nerve. That’s already approved in the US. I’m blanking on the name. It’s approved for opioid withdrawal. There are even other devices that are not FDA approved, but are either in development or approved in Europe. There’s a device called NEMOS. It’s a German device used for epilepsy. As far as the Parasym device, when is it going to be approved? I think that’s going to take probably at least two years.
Why can people get it in Europe then?
If you manage AFib with a multi-disciplinary team, you will get better outcomes compared to a traditional, single cardiologist approach.
For European regulations, you don’t have to show efficacy to get approved. You just have to show safety, so anything that’s safe, like Parasym, can get approved. The FDA on the other hand requires both safety and efficacy to approve a device. It’s different regulations.
European makes a little bit more sense. Any other recommended vagal strategies that you can offer to us and our audience?
Exercise is an endogenous vagal stimulation therapy, and I’m talking about exercising chronically. If you’re on a potato couch and you haven’t done anything and you start exercising strenuously, that activates your sympathetic, but if you take it slowly and chronically, you increase your vagal tone. It’s called endogenous vagal stimulation. Endogenous is a Greek word. It means intrinsic. People do meditation and yoga. Deep breathing is another way, but I wouldn’t recommend it because it can make you dizzy and it brings down your CO2. Those are the main strategies that are nonpharmacological and non-device.
Is there any role for Parasym with persistent atrial fibrillation? I don’t know if that held a place in your studies, or maybe in the future.
All of the autonomic systems diminish as the A-fib progresses, so if you go in from paroxysmal to persistent, the influence of the autonomic tone and the autonomic nervous system goes down. My feeling is that it’s not going to be as important or as useful in persistent A-fib. I say, “My feeling,” because we don’t have any data. We excluded patients with persistent A-fib in our study.
My thoughts on that and why I wanted to ask that question were, is there a way if we were going to cardiovert someone and therefore we’re almost using Parasym prior to and leading up to cardioversion? Would it more likely lead to successful cardioversion and then, of course, the maintenance of sinus rhythm? I would assume that’s not something you’ve looked at.
We didn’t study that. The problem is that we don’t have a good way to assess the impact of the autonomic nervous system in the individual patient. Let’s say, this is 50% autonomically driven and 50% substrate driven, like fibrosis of the atria. We don’t have a good way to do that. Some patients may benefit from this approach because they may still have a high influence of the autonomic nervous system, but on average, I don’t think it will be very beneficial.
What does the future hold for low-level tragus stimulation and the research within that?
We’re doing a lot of research. Our goal consists of two things. One is to find and identify some biomarkers of response that will enable us to better select patients for this therapy. These are the mechanistic part. The other part of our researcher effort is to expand our preliminary study to a larger study using the knowledge we gained from the first study and also from the second study that I just talked about, the mechanistic study, and perform a multicenter study with more patients, which will lead to eventually approval of the device.
What about Ouzo and AFib? Yes or no?
In moderation, yes.
It’s interesting. According to the literature, as I see it, alcohol drinkers up to a certain point enjoy lower cardiovascular mortality. I enjoy drinking alcohol. I don’t drink it that often, but nonetheless, it’s a line that as alcohol consumption goes up, so does A-fib risk.
That is true, so pick your evil. Do you want to have AFib and less cardiovascular mortality, or do you want to avoid AFib but maybe be on the higher side of the risk on that J-curve?
I think your patients, my patients, or those that suffer from atrial fibrillation, those people are more than happy to abstain to see that certainly makes a difference.
That’s a fair statement. If you don’t have AFib, drinking may benefit in moderation, but if you have A-fib, the more you do to decrease that risk, the more benefits you get. Talking about lifestyle modifications, losing weight is an extremely important way. There’s a great group in Australia led by Prash Sanders that showed us losing 10% of your weight decreases the risk of AFib occurrence by 40%. It’s amazing.
One of the things we do in our office, we try and teach people, “If you’re going to go for an ablation, can we make you the healthiest version of you prior to the ablation, so it is of the utmost success rates?” You’re right. It is by losing weight, physical activity, mindfulness, and all these healthy lifestyle changes.
A lot of times, maybe people are suffering and they need to get something done ASAP, but I think if we can get people the healthiest version of them, and if that doesn’t take care of the A-fib, then there is the ablation. It’s much more likely to be successful and also much less likely to have short-term risk and long-term risk as well.
You’re right. The current approach to A-fib management follows the ABC protocol. A is Anticoagulation, B is Better symptom control, but the C, which was added in the 2020 guideline update, its Comorbidities. We came to recognize that addressing comorbidities is equally important to anticoagulation and rhythm control.
Are the cardiologists enacting those new ABC guidelines, or are they still stuck in the A and B?
I think it’s easier to stick to the A and B portion, but we’re lagging behind as a community. In order to address the comorbidities, and I’m not just talking about obesity, but other holistic approaches such as diabetes, hypertension, sleep apnea, all these, you need a multidisciplinary team. It’s been shown that if you manage AFib with a multidisciplinary team, you get better outcomes compared to a traditional single cardiologist managing AFib.
That’s what we teach over here. It was an absolute pleasure. Thank you so much for spending time with us. We look forward to getting more updates and finding out what you’re up to and some of the cutting-edge technologies that you’re developing. Hopefully, with anything and conspiracies aside, we make sure that we have the best and safest technology available to everyone around the world. That’s what our goal is. Again, thank you for your time. We will see you next time. Cheers to your 100-year heart.
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About Dr. Stavros Stavrakis
Dr. Stavrakis is a clinical electrophysiologist and physician scientist at the University of Oklahoma Health Sciences Center. He is an Associate Professor of Medicine and the Director of Cardiovascular Research.
He has been routinely performing complex ablations for the last 10 years. His research has focused on autonomic neuromodulation for the treatment of atrial fibrillation and heart failure, in both animal models and in humans.
His work over the last 10 years culminated in a first-in-human randomized clinical trial, examining the chronic effect of noninvasive vagus nerve stimulation in patients with paroxysmal atrial fibrillation, which was presented as a late breaking trial at the recent Heart Rhythm Society Scientific Sessions in May 2019.
His goal is to continue to explore the role of the autonomic nervous system in cardiac arrhythmias and provide his expertise in both clinical procedures and research activities.
