Marfan Syndrome and Connective Tissue Disorders - Part II

Connective tissue disorders like Marfan, Loeys-Dietz, and Ehlers-Danlos syndromes can affect the heart and aorta, the main blood vessel that carries blood throughout the body. Cleveland Clinic experts discuss imaging, surgical techniques and follow up care for patients with connective tissue disorders in part two of this two-part series.

Meet the Presenters:
Lars Svensson, MD, PhD
Chief of the Sydell and Arnold Miller Family Heart, Vascular and Thoracic Institute

Milind Desai, MD, MBA
Vice-Chair of Education, Heart, Vascular and Thoracic Institute

Schedule an appointment at Cleveland Clinic by calling 844.868.4339.

Learn more about the Cardiovascular Marfan & Connective Tissue Clinic. https://my.clevelandclinic.org/departments/heart/depts/cardiovascular-marfan-connective-tissue

Transcript

Announcer:

Welcome to Love Your Heart, brought to you by Cleveland Clinic's Sydell and Arnold Miller Family Heart, Vascular and Thoracic Institute. This podcast will explore disease prevention, testing, medical and surgical treatments, new innovations and more. Enjoy.

Lars Svensson, MD, PhD:

Today, we're going to talk about Marfan Syndrome and connective tissue disorders. I'm Lars Svensson. I am the Chief of the Heart, Vascular and Thoracic Institute (HVTI), and with me today is Milind Desai. He's our vice chair for HVTI in Education and has a world-recognized expertise in cardiomyopathies, how to treat patients with myectomies, doing some groundbreaking international trials, but also has been very involved with connective tissue disorders and the genetic analysis of these patients, so thanks for joining me.

Milind Desai, MD, MBA:

Thank you for having me, Dr. Svensson.

Lars Svensson, MD, PhD:

Let's talk a bit about the actual surgical options. Historically, the operation of choice was a composite mechanical valve replacement, and many years ago when I was in Houston, I wrote up 348 patients having that. That, at the time, was the biggest series. The problem is obviously, with mechanical valves, patients have to be on Coumadin. We did a recent study that we published a year ago, and we looked at other options for treating patients with mechanical valves other than Coumadin, and we used Eliquis. Unfortunately, it did not work out, so at this stage we don't think that, at least on the horizon, there is any medication to replace Coumadin for mechanical valves, that is the go-to valve, and the results with composite valve grafts are very good. In fact, the stroke rate over time is lower than an isolated mechanical aortic valve replacement. The problem is the Coumadin. Obviously, a lot of young people who present with Marfans are childbearing, young kids and so on, so that's always a concern of it.

The re-implantation operation is a modification of the one that Tirone David from Toronto described. The modification that I introduced, with the idea of having better long-term durability, is reducing the annulus size down to what the expected annulus size is for a certain body surface area. In other words, patients with Marfans are obviously tall, but on top of that, their annulus, which is where the leaflets are attached in the aortic valve, is often very big. It can be four centimeters when it should be, let's say 2.3 centimeters. Part of the operation is bringing that down to a normalized size.

The other thing that was noted in the early experience with re-implantations is that holes can occur into the chambers of the heart when there's not buffering of those sutures that anchor the tube graft outside the valve. When we do the operation, we free up the whole aortic valve around the entire circumference. That whole valve has to sit in a tube, so it doesn't stretch out again or pop out from underneath the graft. The whole valve is wrapped in this tube. Then, we tie down the sutures to the body surface area and re-implant it. But those sutures that we tie down have pledges on them, so those are little stoppers, so the stitches don't tear through the tissue because it's very fragile in patients with Marfans and Loeys-Dietz even more so. You have to be careful that you don't make holes in the heart where you don't want them. Fistulae is what we technically term them or various other spaces or leaks from the re-implantation. Those are two of the aspects of the modification.

Now, what are the results? A couple of years ago, we wrote up all our connective tissue disorder patients, 214 operated here at the Cleveland Clinic with a re-implantation operation, the biggest series in the world, no operative deaths and the long-term survival was excellent. Also, on top of that, the freedom from re-operation in the patients with connective tissue disorders was 97% at, I think, it was 12 years, might have been 15 years in that group. The point is we were always worried with patients with Marfans that the tissue was very fragile, including the leaflets, that they would not stand up to a re-implantation operation. That has been shown now that our fears or concerns about that do not hold true. In other words, in patients with connective tissue disorders, the chance of a long-term failure at about 15 years is 3%. Really holding up very well and obviously, patients then don't have the mechanical valve, they don't have to be on Coumadin. Their risk of stroke is low, their risk of clots forming on them is lower and the risk of infection on the valve is also lower. The long-term results are very good with re-implantation in both patients with Marfans and Loey's-Dietz syndrome.

Let's talk a bit about follow-up of patients who've had their surgery and what medications you recommend or what you do for your patients as far as beta blockers, losartan, monitoring how often you follow your patients, MRIs, et cetera.

Milind Desai, MD, MBA:

That's an important point. This is a lifelong disease and it's not a one-and-done situation where you can be lost to follow up. We see these patients, we try to see them immediately in the post-op setting. They obviously have to be seen at six weeks or thereabouts, but in the big picture, we try to see them annually with imaging, precise imaging. What I tell patients is we need to have touch points at periodic time points, typically annually, because we need to be doing imaging that can be compared on similar scanners, similar folks imaging it. You obviously have to look at the graft, but also the valve, and make sure it is holding still and not leaking. If it is leaking, it is no more than mild or so. We clearly do echo. We are liberal users of CT for follow-up because the resolution for aortic follow-up is excellent.

But sometimes, or often, if the patient is younger, it is important to recognize that sequential CTs may provide a lot of radiation. Of course, with our CT scans, we are very stringent with our radiation dose. the radiation doses are typically not very high here, some of the lowest on the planet. 

But even then, there may be younger folks where we put them on a serial MRI imaging process. Typically, we do it every year or thereabouts, make sure the other parts of the aorta are stable. As Dr. Svensson mentioned, sometimes there may be aneurysmal degeneration, not very frequently seen, but often enough that we put them on a follow-up protocol.

In terms of the other things, as was alluded, they may have lens problems, other spinal problems or pulmonary problems. It is important that these patients also periodically see their ophthalmologist who is experienced in dealing with connective tissue disorders, as well as orthopedic surgeons who know how to handle these disorders.

The other aspect is tight control of their blood pressure. We call that impulse control. Heart rate and blood pressure, they are two of the drivers that can potentially aggravate a fragile aortic ecosystem, for the lack of a better term. The two class of drugs ARB (Angiotensin II Receptor Blocker), so Losartan, Cozaar and beta blockers, Metoprolol, Atenolol, we use them liberally. I always tell patients to maintain their ideal heart rate in the fifties and sixties, blood pressure according to guidelines. Maintain a tight control of their comorbidities, like obesity. I mean, don't forget the other things simply because you have an aortic aneurysm. Overall, I think the key message is to stay connected with us, with a center of excellence.

Lars Svensson, MD, PhD:

Well, thanks, Milind. I think those are very important points for follow-up of patients. Let me just also mention some of the comorbidity things, as Milind mentioned, orthopedics and eye follow up and specialists in managing those patients. We certainly have them here, but something as a great interest to Milind is the cardiomyopathy. Patients with connective tissue disorders can develop intrinsic, left ventricular dysfunction as a cardiomyopathy irrespective of whether the patient has valve or heart disease. That is a feature of Marfans.

It's fortunately rare that we see that, but Milind, I'll give you a chance to comment about that. The other problem is that we have to follow the mitral valve because that may over time get involved. Also, something that is not often recognized is that we get baseline pulmonary function tests on all our patients. Usually, we see some dysfunction, the breathing tests, they're usually not bad. But over time, patients with particularly Marfans, do potentially develop COPD or emphysema. It's something to track over time.

But Milind, let's just talk a bit about the cardiomyopathy. I know of just a couple of patients we've had to do heart transplants on for the cardiomyopathy, as it's pretty rare. Some comments about that.

Milind Desai, MD, MBA:

It is rare mercifully, but also it may very well be, in the past, like you alluded to, the life expectancy was lower, so maybe there was not enough time for these other comorbidities to accrue. Now that the Marfans and connective tissue patients are living longer, it might be important to keep a close eye on all these other comorbidities, other diseases that may crop up.

So again, mercifully right now it is our experience that to me, the way I look at it, in a Marfan or a connective tissue patient is the aortopathy is by far the most common presentation. Then a small proportion have concomitant mitral valve disease, and even a much smaller proportion have a concomitant cardiomyopathy or may develop downstream cardiomyopathy. But this underscores the importance of us being on top of their follow-up, not just imaging of the aorta, but looking at their echoes and periodic MRIs to make sure the cardiomyopathy does not creep in, and clearly pay attention to the mitral valve.

Lars Svensson, MD, PhD:

Great. One other thing. While you were talking, I was just thinking about this. Patients with Marfans also have a tendency to have a prolonged QT interval, which is something that can and potentially needs to be treated. It's something to keep an eye on. There was a paper many years ago. I used to get 24-hour Holters on all my Marfans patients because I thought that that was potentially a problem and has turned out that occasionally that is a problem.

So, Milind, you mentioned you're three times more likely to survive for most heart surgeries if you come to the Cleveland Clinic. That's based on comparison with the average outcomes in the United States for heart surgery using the STS (Society of Thoracic Surgeons) criteria of observed to expected [mortality]. Simplifying the statistics, that’s three times more likely to survive than any other average hospital in the United States.

Obviously, here we haven't had any deaths, fortunately, for Marfans and Loeys-Dietz re-implantation surgery. As I said, we do see a lot of patients who, unfortunately have had previous operations, including for aortic dissection, and then the surgery gets much more complicated. You have to then look at aortic arch surgery, potentially barraged artery surgery, descending thoracoabdominal surgery, often reoperative surgery, and that in itself can require multiple operations over time. Any comments about why patients with connective tissue disorders should come to the Cleveland Clinic?

Milind Desai, MD, MBA:

Yeah, I think you mentioned, the point is this is a team sport. Managing this complicated group of patients is a team sport. It requires key players in various aspects of management, cardiology, imaging, cardiac surgery, as well as the others, orthopedics, infectious disease, et cetera. The ability to mobilize a team that works at the highest level in a highly efficient manner. No place does it better than the Cleveland Clinic, hands down, no question about it.

Another important thing we need to recognize is patients need to know. Another powerful thing I tell patients is, if you are a Marfans patient within evolving aortopathy and you get into a program of periodic follow-up and at a place like the Cleveland Clinic, including periodic imaging, and you take our advice, the risk of you presenting with a downstream dissection before we would have electively fixed your aortopathy is extremely low. It's extremely low.

I think that's something important that speaks to the preemptive, proactive approach that we take and are able to mobilize the team. Now, there are patients who we may see for the first time ever in the setting of an acute emergency. Our ability to auto-launch you to our ICUs, to take you to the OR, to mobilize 24/7/365, no matter rain or shine, is better than any other place on the planet.

Preemptive surgical, as well as in the midst of a crisis, our outcomes speak for themselves. You already mentioned about the surgical outcomes, but what it takes to get to that surgical outcomes, this is a special place for that.

Lars Svensson, MD, PhD:

So, Milind, just on that final point, you looked up all our patients who had surgical procedures for Marfan syndrome, and this was not just re-implantations, but all procedures which far exceeded any of the other leading institutions or those that used to lead in the field of Marfans. We by far now have the biggest series of patients who have undergone procedures for Marfans. Do you want to comment a bit about that? It was something like 1,100?

Milind Desai, MD, MBA:

Yeah, a little over 1,100 patients. Again, as I alluded to the outcomes of preemptively done surgery. We see you, we evaluate you, we say, "It is time for you to have surgery." The outcomes were excellent, excellent, excellent. Even the ones that came here emergently, their outcomes were - of course they're not going to be as good as the preemptive surgery if you are in the midst of a dissection or a rupture or what have you. But they were substantially better than the rest of the population.

The most important thing I learned from that paper was, as I alluded to earlier, more than 50% of them, their aorta at the time of their rupture was lower than what the guidelines would've recommended as a threshold. To me, that reflects that we have to be a little bit more aggressive in our mindset as we are evaluating these patients. Look for risk factors more aggressively and not perhaps wait till five centimeters. Especially if you are at a place like here, perhaps jump into a preemptive operation slightly earlier. Guidelines are there, but we have to be very nuanced about how we apply those guidelines, especially in a place like this.

Lars Svensson, MD, PhD:

Well, great. Well, thank you for listening to the segment of Love Your Heart. We appreciate the time you've spent listening to us. We are always available for you to consult and evaluate any potential connective tissue disorders, Marfans and Loeys-Dietz being the most common ones. If you need to have genetic testing at the same time, we certainly can do that. Just let us know what you would like to do. We typically will get the pulmonary function tests, the echo and the CAT scan as a starting point for assessment. Thank you for listening to us.

Milind Desai, MD, MBA:

Thank you very much.

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