Mechanisms in the Development of Post Operative Atrial Fibrillation

In 2015, as a Medical Instructor and Research Fellow at Duke University Medical Center, Michael W. Manning, MD, PhD, began to revisit a research study he had investigated during his PhD training, where he used angiotensin II infusions to increase blood pressure and look at its inflammatory effects in a mouse model for abdominal, erratic aneurysms, and looked for ways to adapt that question to focus on cardio pulmonary bypass. With the help of an IARS Mentored Research Award that year, Dr. Manning was able to embark on a study focused on “Mechanisms in the Development of Post Operative Atrial Fibrillation.” He hypothesized that if you go on bypass, you’re going to set up an inflammatory response, and being hooked up to the heart-lung machine is going to trigger a cascade of events that the body is going to mistake for acute hemorrhage and acute blood loss. The angiotensin II is then going to be up regulated and a side effect of that up regulation is going to be local fibrosis in the heart which is being operated on. Dr. Manning’s investigation focused on a rat model, which was the smallest animal for which they could miniaturize the heart-lung machine. Unfortunately, this model proved extremely challenging. The study required aged rats which were extremely expensive to obtain and complex and tedious to utilize with only one local lab member with the expertise to operate on the rat. Although they eventually completed the research and met the initial hypothesis, Dr. Manning wasn’t able to translate those outcomes into a bigger project with other funding entities. As a result, today as an Associate Professor of Anesthesia at Duke University, Dr. Manning has shifted his research focus away from basic science research to translational research. Now he helps to translate more advanced bench science to clinical application, primarily centered around volume and fluid management around cardiac surgery to preserve kidney function.

1. What is your current position? How long have you been in this position?

I’m now an Associate Professor of Anesthesia at Duke University. I’ve been at Duke since I came for my clinical fellowship in 2011. I started off with a one-year clinical fellowship, and then a two-year research fellowship. That then led to me staying on in the role that I have now.

2. What was your role when you were first funded by IARS?

I was listed as medical instructor and a research fellow.

3. What was the goal of your initial research project? Was it met?

Angiotensin is a stress hormone that typically is released in the body in response to hypotension and will signal the kidneys to release aldosterone (ALD), which will then in turn trigger the kidneys to hold onto salt and hold onto water in a mechanism to auto regulate blood volume. So, it increases circulating fluids.

Angiotensin, being a stress hormone, also has pro-inflammatory signaling that’s associated with it. If you were in a fight or flight, think evolutionarily if you got cut, angiotensin releases to help compensate for the blood loss to withhold water or hold on to water and hold on to salt. But it also triggers local inflammation in the tissues for wound healing and wound stabilization.

We were interested in looking at research that I had done as part of my PhD work years before – how cardio bypass would trigger circulating angiotensin II levels to alter fibrosis of the heart and to possibly trigger atrial fibrillation. The hypothesis was if you go on bypass, you’re going to set up an inflammatory response, being hooked up to the heart-lung machine is going to trigger a cascade of events that the body is going to mistake for acute hemorrhage and acute blood loss and the angiotensin II is then going to be up regulated and a side effect of that up regulation is going to be local fibrosis in the heart, because that’s being operated on. That’s where it’s going to be centered the most and that’s going to increase the risk of postoperative atrial fibrillation which occurs in 30-50% of patients after surgery.

The IARS grant was to look at a rat model. We would put rats on cardio pulmonary bypass, and then looked at angiotensin production in the hearts and the tissues and look at fibrosis within the rat heart. Then, we were starting to collect human atrial tissue samples pre-bypass to post-bypass. What we found was, in the rat hearts, angiotensin II is up regulated and fibrosis was occurring in the hearts within 6 to 12 hours after exposure to the heart-lung machine, which is keeping in time with the observation of atrial fibrillation onset in humans. Then, in the human atrial biopsies we were taking one immediately before bypass as part of cumulation, and then immediately after bypass. The tissue angiotensin production was increased. So that’s as far as we got.

We were able to establish the hypothesis and met the hypothesis from that standpoint, it was a success. We weren’t able to translate it into a bigger fundable project with other entities like we wanted to. I couldn’t turn it into an RO1, but, for the aspects of the IARS grant, yes, it was a success.

4. How did your findings impact patient care?

A lot of it is in how we manage medications around cardiac surgery time. The literature that has come out of the cardiology specialties, will lump angiotensin receptor blockers and ACE inhibitors together as a drug you should not take going into heart surgery. I’ve always been very critical of that position because an injury tensor receptor, block curve and an ACE inhibitor do not work at the same control points in the pathway to generate angiotensin II or to suppress the generation of injured angiotensin II. So, you can’t make a blanket statement saying you should be off of them. We had published a paper before the grant that looked specifically at patients that were given either ARBs or ACE inhibitors going into surgery, and the patients that got ARBs did better. The patients that got ACE inhibitors did worse. We felt that was very telling.

If you were to take an angiotensin receptor blocker, then the angiotensin II that is produced during cardiac surgery is then shuttled down a different signaling pathway that is actually anti-inflammatory and anti-fibrotic, it is a beneficial pathway. If you were to give an ACE inhibitor, then you lose the benefit of the anti-inflammatory processes, and you then default to a much greater level of inflammatory response. So, it actually makes things worse. The research could have benefited from that. I think it would have been a good model to use for evaluating pharmacological interventions to prevent post-operative atrial fibrillation.

5. How did your research impact the field of anesthesiology?

I think it would have given us more insight on how to manage perioperative surgical assaults as it relates to the inflammatory cascade so we could better advise patients what medications to take and how to hopefully mitigate some of the effects of the surgical assault that the patients undergo. Improved recovery would be the ideal hope.

6. How did the award affect your research/professional trajectory?

An award like that, it’s instant validation of your ideas. Because you submit a grant, and it’s peer-reviewed. Experts in the field will look at it and say, “Yeah, this is important to throw a dollar set at.” Any time things get funded, their value obviously goes up. So, the personal trajectory, the professional trajectory, it helps launch you. People start taking you seriously and listening to you, and you’re engaged in the network around the university. That was good.

Now I had grants back in grad school and postdoc grants. So, for me, it validated what I’m supposed to be doing. But outwardly, the philosophy was that nobody believes it until you get a grant. It helped launch my early career and get me to where I’m at today.

7. How do you feel about having received the IARS Mentored Research Award?

I feel really honored. Part of me is regretful that I wasn’t able to deliver on the promise and become a truly independent investigator like I had hoped. The mentor that I had also lost their R01s. Funding at that time was difficult to get. It was frustrating.

8. What drew you to anesthesiology and to your particular area of research?

So, I did a PhD first, and it was cardiac physiology. That’s where I did mouse models using angiotensin II infusions to increase blood pressure and look at the inflammatory effects of angiotensin II and we developed a mouse model for abdominal, aortic aneurysms.

Then I left that and went to medical school. I actually wanted to be a cardiac surgeon. So, I started off in general surgery and found that I couldn’t do the research that I wanted to do because of the requirements for patient care and the surgical life just wasn’t going to cut it. My wife is actually an anesthesiologist as well. So, she reminded me that some of the most fun I had was back in physiology in the dog lab, doing whole animal specimen preps. She said, “You should look at anesthesia.” So, I did and instantly fell in love with it, and it was just applied physiology, which was my research background. So, I made the switch into anesthesia, but I always loved cardiac physiology, and to me that was something that was very intuitive and everything about it just instantly clicked and made sense, and it was fun to teach. When I was in grad school I taught medical physiology, and I taught sections of cardiac physiology to the medical students.

So, the natural evolution was to pursue a fellowship in cardiac anesthesia, and so that led me to coming to Duke, and then the opportunities for research here as well. Then, I just circled back and pulled a lot of the basic science stuff that we had done with angiotensin in the mice and the inflammatory processes and applied them to cardiac surgery. It’s a long road to get there, but I made it. The skills and experiences I developed in both my PhD and MD training as well as the research experience gained through the support of the IMRA have set the ideal stage to help bridge the gap between basic science research and clinical research, serving an important need in the anesthesia research field.

9. Has your research subject area evolved since the award?

Unfortunately, we met a lot of walls. The basic science approach that I was used to in graduate school was a very different mindset to get papers published and to get grants than what the clinical application was. It was very, very difficult to convince clinicians that the basic science was sound and could have a role in clinical therapeutics. So, I was unable to secure additional funding to support the project and ultimately had to leave the lab because of it.

But what we’ve been able to do is highlight the work we did and try to continue to push others to look at these effects.

Some of the biggest challenges were the animal model that we used was very complex and tedious to utilize and while we ultimately got it to work, it was very cost prohibitive, and time prohibitive, way more than I estimated. There was only one person that we had that could do the animal operations and this person had other roles in the lab to do, and so getting a series of animals done in a timely fashion was a real problem.

Rats were the smallest animal that we could miniaturize the heart-lung machine down to, and rats are unfortunately very, very expensive to house and hold. We needed aged rats so you could either spend a lot of money to buy research rats that are aged up, or you could buy a colony of young rats and then have them sit around and age up. Everything centered around this; the animal model was challenging.

If I had to do it over again, I would have focused everything on acquiring human tissues and spending a lot more time on that instead of starting with trying to understand the mechanism, and then prove that. It would have been better to acquire human tissues and do a lot of initial characterization work, then to prove the clinicians and surgeons and the funding bodies that we were going after, that this is a real thing. There’s an opportunity to intervene.

So, the next step would be to just forget the rats. Let’s do a trial with off-the-shelf ACE inhibitors or angiotensin receptor blockers, and you could have done a much better job advancing things that way.

I still do research. I do more translational research. So instead of being at the bench, I spend more time taking things that are more advanced from the bench science and applying them clinically in the OR suites. It’s mostly centered around cardiac. It’s volume and fluid management around cardiac surgery to preserve kidney function.

So, a lot of the skills and a lot of the conversations that I had, and the skills developed during the IARS funding time certainly are still used in what I’m doing now. I originally wanted to be a bench-to-translational kind of a guy, but now I’m more of a translational to the clinical side, the old idea of an MD-PhD taking a clinical question back to the lab, sorting it out, coming up with the solution, then taking it back to the clinical realm.

I’m now partnered with basic scientists that have the better experience and bandwidth to do these things. And I meet them in the middle of that translational juncture and then I take it to the clinic. It’s a much better approach for success.

One of my mentors really early on, at the very start of grad school, used to say that if you had both degrees, if you did them together, you wouldn’t have the clout. But if you separated them, and did a pure PhD and then you did pure medical school that you would always be able to move within those circles of each with a lot more peer respect, and they wouldn’t look at you as a watered-down either clinical doctor or watered-down research scientist. That’s very true of me. I can have those conversations with each group very well, because I’ve done both sides. I hope that I’m helpful back to the basic sciences and giving them perspective and helping pull them more into the clinical side where they don’t go. Then, helping some of my clinical colleagues that do research, but who don’t have that bench background, push them the other way.

10. What do you hope for the future of anesthesia research?

I would love to see it be funded a little bit more separately than it is typically through the national system. The society grants that are available to anesthesia, certainly, IARS and FAER grants are really key, but the dollars that are associated with those grants and the Society for Cardiac Anesthesia Grants, and the American Heart Association has a component for cardiothoracic surgery and anesthesia, to see those values go up a little bit in keeping with the cost of things a little bit more.

I would love to see specific grants for the interface of a medical student becoming an anesthesia resident, that would help bridge them, and not maybe necessarily fund a project, but fund the training and the skill set to do research properly. Part of a pure PhD is very rigorous – this is how you do literature research; this is how you research manuscripts; this is how you ask a very good research question. And, it’s very regimented, a very prescriptive methodology to teach that. It’s not taught at the depth it should be in medical school. It’s very glossed over in residency. Depending on which residency program you’re in, it’s either not taught at all or it’s taught at a very light level. So, if FAER or IARS has a mechanism that would provide deeper, more enriching research skill set that when you are a resident, then grow into senior years and then into a fellowship, you’re coming to that experience with the skill sets already there that they can then build on. I think that would be very important.

The other reason I think that would be good and important is that a lot of people that I’ve seen and talked to and taught when they’re in undergrad, they do research to tick a box. They’ll go into somebody’s lab and they’ll want to go to medical school, and they say that research is important. So, they want to do a research project, and they have absolutely no clue about what research is or what it entails, or how it’s conducted, or if you will meet the right faculty member that will sit down and take the time to teach them. It’s important. You will see them have the smile of recognition across their face like, “I get it, right?” If you give somebody a set of skills so that they can ask the questions that they are interested in, rather than going blindly into somebody’s lab and doing something that they don’t understand, that they end up not liking, and it taints the experience in the negative light. So that when they leave the research experience, it’s, “I don’t ever want to do this again. I even hate the word. Don’t say research to me.” I think you would change that perspective that a lot of medical students and residents end up having. You would have a very protected tunnel to take those with the budding interest into this conduit the right way. Build them up, give them the right skill sets, then they can go out the other end and have a little bit more understanding of where to go next and then match them with faculty that are asking the questions that they’re going be most interested in.

So, the second big iteration of how I would change anesthesia research, would be to have some kind of national database of anesthesia researchers, and what they’re doing, almost like the old JCPenney’s Christmas catalog. So, you could flip through and see everybody who’s doing what and maybe who’s near you that you wouldn’t know otherwise. Then, start fostering those interactions to those relationships. I would love to have a research fellowship that focused on the integration of the research with the clinical practice. This was something that took me 4 years of grad school, 4 years of med school and several years of residency, and that experience somehow gets laser focused and do it over the course of a year, where people see how the research and the clinical side interface. Once they have this skill set, then ideally they’re working with somebody that’s going to let them ask the questions that they’re interested in and have that support structure to grow them.

The last component of that would be for them to see where in this continuum they most think they will fit in and feel comfortable. So, for me, ultimately it was translational on the clinical side. The spectrum of a pure, pipetting test tube researcher in anesthesia, then there’s pure clinical researchers just taking patients in and measuring their blood pressures. And then there’s everything in between. So, letting you see where in that rainbow you’re going to best fit to really shine. That would be the third component. So that’s how I would like to see anesthesia research change.

11. What is something that someone would be surprised to learn about you?

I am an award-winning photographer. I take mostly landscapes.

There is an old tobacco production warehouse complex in Durham that I took a photo of, and I turned it into a big canvas. It’s the old Lucky Strikes and it’s now the American Tobacco campus. But in the middle of this complex was an old power station and just to the right side of this very old brick and mortar industrial place, they had a little restaurant for the workers called Downstairs, because it was down a little flight of stairs. It’s an old painted wall that has the menu on the outside of it, and the prices,  a cheeseburger was 10 cents. French fries were a nickel.

It’s really, really old, and I framed it so well, and the lighting was perfect, and the shadows and angles. It’s very industrial with old rusted pipes and the staircases, and the red brick of the building, and then the old faded sign is still very legible, and it’s just a gorgeous print.