The Importance of Congenital Heart Disease Research

“It is a great thing to make scientific discoveries of rare value, but it is even greater to be willing to share these discoveries and to encourage other workers in the same field of scientific research.”

-Dr. Will Mayo

Medical research is an integral component of the advancement and effectiveness of medicine. In this Q and A with Mayo Clinic cardiologist Alexander Egbe M.B.B.S., research within the field of Congenital Heart Disease is discussed, including current research studies, important innovations both now and in the future, as well as the goals of this research to not only impact Mayo’s patients, but patients across the country and world.

Q: What are you currently researching in Congenital Heart Disease?

A: I’m working on a number of things. Of all the 15-key diagnosis in congenital heart disease, my research focus is on three main disease types. One is tetralogy of Fallot, which a right sided disease, the second one is about coarctation of the aorta, which is a left-sided disease, and the final group is patients who have a complex single ventricle that have had Fontan operations.

Q: What does the research of these three groups, those with tetralogy of Fallot, coarctation of the aorta, and patients with complex single ventricle that have had Fontan operations, entail?

A: Each group has different things. For example, with tetralogy of Fallot. Patients who have tetralogy of Fallot have their surgical repair sometime in infancy. By the time they come to us as adults, they usually have pulmonary valve regurgitation, which is leakage of the pulmonary valve, and leads to enlargement of the right side of the heart. This is a trigger that leads to end-stage heart failure or sudden cardiac death. It is because of this, that the average survival of patients with tetralogy of Fallot is 55 years, that’s compared to 75-80 years in the general population. My research target, is to find ways to prevent end-stage heart failure, and sudden cardiac death which are the two reasons why they die in their 50’s instead of their 70’s. To do that would be to focus on two things, one, best way to identify and treat pulmonary hypertension, so we don’t do the procedure too early or too late. Secondly, identify the best way to find people at risk for sudden cardiac death, and do something about it because that’s one thing that doesn’t give you a second chance. So identifying those who are at risk, and doing an ablation or putting ICD’s (implantable cardioverter-defibrillator) in them. Everything I’m doing is like a multi-stage process of actually finding people at risk. We call it risk stratification, finding out at what point is the benefit of doing something outweigh the risk of the procedure. That’s what we are trying to figure out. This will take years to actually make clinical impact.

Q: What is a major goal of congenital heart disease studies?

Once you find out something new, it takes awhile to get assimilated as standard of practice across the country. That’s what will affect the population outcome. Our goal is not to just improve the lives of patients who come to Mayo Clinic, but improve the life of every person with tetralogy of Fallot for example, in North America and in the world. To do that, it will be contingent on people imbibing what we find out from here. So for instance, from our studies we’ve shown that doing pulmonary valve replacement which is a surgical procedure that you use to treat pulmonary valve leakage, that you use to treat patients with tetralogy of Fallot, we suspect that the current guidelines about when to do the procedure is too conservative, that people are undergoing this procedure too early and they probably could afford to wait. If you do it too early, these valves don’t last forever they last around 12-13 years and the valves with fail. Then you need to go for a second procedure which is usually far more technically difficult than the first one, and if you look at the average age of a person that goes for pulmonary valve replacement, they are around 30 years old. So then you need to put in a second valve when they are 42. If you put in a valve when they are 42, then they go in for a more risky procedure in their early 40’s and then the valve will fail in 12 years and they’ll be in their 50’s. By the time you do this procedure a third or fourth time the risk becomes prohibitive that you can’t even do it. So you factor in the calculated risk of the procedure and if you can not afford to wait it’s better off for the patient.

The second problem is if you put in the valves they are at risk for prosthetic valve endocarditis which has high mortality rates. So if you can buy some time before putting in the first valve, you’re certainly at risk for infection. What we have found out here so far in our practice, is doing the procedure later might benefit the patient and that is influencing out clinical practice. As we publish these studies, we are hoping that people will read it and will apply it to their own clinical practice and over time as more people are doing studies that confirm what we have already found, it might result in changes to the guidelines. So to answer your question, what we are doing is influencing our practice, already, which over time, in the space of two or three years we’ll be seeing the affect on outcomes in our patient, but more importantly the end goal is to influence practice in the whole country and change outcome for patients in the whole country.

Q: So eventually your end goal is to not only change and improve the care across the country, but across the world as well? 

A: Yes, exactly.

Q: Great. As you work on these research projects, what are the positives and negatives of the current state of CHD research? What are some problems you encounter?

A: If you look at congenital heart disease research as a whole, it is still very much undeveloped compared to other areas of cardiology just because it is a young specialty compared to coronary heart disease and heart failure and everything else, that’s one problem. Two, is that congenital heart disease is not as common as other heart diseases so research has been hampered by small patient size. That’s a problem across the board everywhere. Mayo Clinic has an advantage, and that is it is one of the first centers to do congenital heart surgery in the world so they’ve had 50 years of experience doing this. With this, we have 50 years worth of clinical data floating around somewhere. Going back to when I came to Mayo Clinic in 2014, the old model of just figuring out how I’m going to look for the patients to do the research was what was done everywhere else, that’s what’s been done here. So the innovation I brought to the table when I came here was establishing something we call “MACHD,” Mayo adult congenital heart disease database. This is a comprehensive database that contains the data of every patient seen here from January 1, 1990. That’s already 28 years worth of data. So that’s everybody that’s been scene, every piece of clinical data they have, is logged in a database with a unique ID. By doing that what we found out was that it dropped the time used to do research, by 80 percent, by a factor of four. A good way to measure that is that prior to 2014, the average publication from our congenital heart disease practice was about four or five papers a year. In 2016 we published about 13 papers, 2017 we published 18, and last year, which is 2018 we published 22. We spend more on this this year, and at full production we should be at more than 30 papers every year. What we need is data, data will influence our practice.

Just as the MACHD database was one of the biggest innovations that improved productivity, the other big innovation that came in late last year, into this year, was establishing prospective registries. So that’s a registry in the cath (catheter) lab and the echo (echocardiogram) lab where we are not just waiting for things to happen, where we can collect the data to place in the MACHD database, but we are actually influencing things to happen. We are enrolling patients in prospective studies. To do that we need money, and we have several lines of funding now, from multiple grants including the NIH and some external which hasn’t happened before, this is the first time we have had this funding, and now this money is being used to fund the non-invasive perspective studies in the echo-lab, and the invasive prospective studies in the cath-lab, so we now have an exercise echo-program.

What we are hoping will happen by this year, is we would like to establish a biobank. In North America, there is only one center that has a biobank, that’s the Harvard program and in Europe there is only one in Amsterdam, so this would be a way to store blood samples from patients indefinitely. This would allow us to run multiple biomarkers that would help us figure out who is at risk, and who should we treat differently, to try to individualize patient treatment. More biomarkers are being invented every other year, so if you already have the blood samples saved, and they invent a new biomarker in ten years, all you have to do is go back and test the sample and make risk stratification. It is something that has been done in other areas of cardiology, and in congenital heart disease we think it will be a game changer going forward.

Q; Are there other potential innovations that you see coming down the road, or is biomarking the big one right now?

A: Yeah, so patients die from heart failure, which is a plumbing problem, or sudden death which is an electrical problem. So when they come into the clinic we do an ECG which tells us what the heart is doing within the ten seconds it take to do that. Sometimes we do a whole time monitor, if we are worried and that records the heart rate for about 24 hours. So there is a very nice heart monitor that can record the heart rate for 30 days called the bodyguardian. It’s used in clinical practice here at Mayo. We have access to funding, so that sometime in the summer or fall, we can establish a reading laboratory where we can get a baseline of our patients who are normally at risk for arrhythmias by doing this 30 day monitor on as many patients as possible. The goal is to identify patients who have brief, asymptomatic arrhythmias, so they are not even aware the have it. The question is, why is that important? It’s been shown, in the non-congenital population, that having brief atrial fibrillation for a few minutes that you’re not aware of, still increases your risk for stroke. Because you don’t know it’s happening, it doesn’t save you from a stroke. How much is that a problem in our population? We don’t know, and you won’t know until you look.

Q: At Mayo, how many congenital heart disease research studies are happening right now?

A: I spearhead most of the research, so about 90 percent of the studies that are actually going on, are spearheaded by me. Last year, of all the publications that happened, I’m directly involved in, about 95 percent of them. So ongoing, the way to look at it is, are they retrospective studies, studies that involve the MACHD database where are going to look at data that is already collected. Those we are doing so quickly that we are averaging about two a month with a minimum of 24 a year. We crossed the 24-barrier last year and we have that as a goal moving forward, so that’s one thing. The prospective studies, where you are collecting data as you are going along, those ones take years to complete one study. Right now, we have eight that are perspective and ongoing. One is funded by the NIH, others are funded by a number of funding bodies, from Mayo and outside Mayo. So we have all these things going on and there is a clinical trial that we’re doing that has been funded by the Mayo Clinic, where we’re looking at people with Fontan physiology to figure out a way to manage liver disease. This is the first randomized trial to look at the effects of it on liver disease, so that trial will be ending in September of this year, so we should have the result by the end of the year.

There is also a second funded studied by a benefactor grant from outside Mayo, that is looking at patients with tetralogy of Fallot and their exercise capacity, so the first trial I mentioned, that looked at liver disease, runs about two years, ending in September, this one has also run about two years and will be ending in December.

We also have a new study that is being funded by the Mayo Clinic Foundation for Research. And that one will be looking at exercise testing in the cardiac cath-lab, with patients with coarctation of the aorta and tetralogy of Fallot. That funding was approved last month, we have yet to enroll our first patient but sometime in February or March that will start.

Altogether we have eight prospective studies, and would like to start more of them.

Q: Any final thoughts?

A: To wrap everything together, there is a need to use what we already have, which is a lot of data. So having that MACHD database was a major innovation that moved things from 5-6 studies a year to close to 30 studies a year within a short period. Perspective studies are good because it gives you a different type of data, and that kind of sets us to be a site to get a lot of funding from the government and from other sources in the future for clinical trials. Then the biobank, that I talked about, is going to be the next generation things, that is going to come at some time in the future, that if we set it up, we will be the lead site in the country, and set up in a model that other people can copy.

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