COMMENTARY

Marfan Syndrome: New Challenges

Bernard J. Gersh, MB, ChB, DPhil; Juan M. Bowen, MD

Disclosures

April 07, 2014

Editorial Collaboration

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Marfan Syndrome: Frequently Undiagnosed

Bernard J Gersh, MB, ChB, D.Phil: Hello. I'm Bernard Gersh from the Mayo Clinic and with me today—and it is a great pleasure to have him—is Dr Juan Bowen, who is director of the Marfan and Thoracic Aorta Clinic. Juan, this is a multidisciplinary clinic, correct?

Juan M Bowen, MD: Yes, it is. It involves cardiologists, geneticists, imaging specialists, and cardiac surgeons. I am a general internist, but it is a multidisciplinary clinic, and we use all the disciplines.

Dr Gersh: How frequent is Marfan syndrome?

Dr Bowen: I am glad you asked that question, because this is an important condition. It affects about one in 5000[1] people, and we are discussing it today because the cardiovascular aspects of Marfan syndrome, although not the most visible, are the potentially lethal aspects of it. It is also interesting that it is estimated that perhaps half of the people in the United States with Marfan syndrome have not been diagnosed. They don't know that they have this potentially lethal condition.

Dr Gersh: That includes a fair number of athletes, because they are very tall?

Dr Bowen: Yes, and every few years something bad happens and it's in the newspaper. The most visible aspect of it is the musculoskeletal aspect, where people are very tall and thin, with very long fingers, and very long limbs.

In 2010,[2] the diagnostic criteria were revised because a lot of Marfanoid-appearing people do not have the Marfan syndrome, and the new criteria emphasize the cardiovascular aspects—the aortic root and the newer, better, more available genetic testing.

Sudden Death in Marfan Syndrome

Dr Gersh: Before getting into the cardiovascular aspects, I thought of an analogy with hypertrophic cardiomyopathy, which is also very often undiagnosed. It does affect athletes, and it may cause sudden death. You read about it in the newspapers. How often does Marfan’s cause sudden death?

Dr Bowen: It happens with reasonable frequency. It is not one of the most common causes of sudden death, but patients who experience dissection, unfortunately, even aortic rupture, may die very fast. That would be the main mechanism.

Dr Gersh: As cardiologists, what should we look for?

Dr Bowen: First of all, we need to recognize the musculoskeletal features. That may not be the job of the cardiologist, but sometimes it will be. Usually the patients will have been referred, and we need to understand the importance of echocardiography and other imaging, the central issue being the aorta and the aortic root in particular. Most patients with Marfan syndrome have disease of the proximal aorta and a few have disease of the distal aorta.

Of interest, now that patients with Marfan live a lot longer, newer problems are arising, such as distal aortic conditions, musculoskeletal problems, and ocular problems, which get worse as they get older. So the natural history of the condition is changing because of the success of medical and surgical treatment.

Dr Gersh: How common is chordal rupture and severe mitral regurgitation?

Dr Bowen: That aspect of the Marfan syndrome has not been fully studied, not as much as it should be. Right around 30% to 40% of the Marfan population will have mitral prolapse.[3] Because it is a generalized connective-tissue problem, the people who have mitral prolapse tend to have bileaflet prolapse, and they tend to have more progressive mitral regurgitation than the usual person with mitral prolapse.

Dr Gersh: I heard you and your colleagues present and say that it is striking that here is a disease where the natural history has changed dramatically over the past 20 years. How has it changed?

Improvement in Surgical Repair

Dr Bowen: The primary improvement was the realization in the 1970s that the aortic root could be repaired effectively using the Bentall or composite graft technique.

Dr Gersh: So, 20 or 30 years ago, what was the average lifespan of a person with Marfan syndrome?

Dr Bowen: Most died in their 40s.

Dr Gersh: And now?

Dr Bowen: They have a normal life expectancy.

Dr Gersh: That is amazing, in 20 years.

Dr Bowen: With the development of this operation by Hugh Bentall from London, all of a sudden the repair of the dilated aorta became possible, and with increasing experience and time, the thresholds for when that repair should be done prophylactically have progressively lowered. Today, it's routine to have an operation prophylactically when the aortic root reaches 45 to 50 mm in certain cases. Formerly, it was 60 mm.

Dr Gersh: Do you ever wait beyond 5 cm [50 mm] in a patient with Marfan syndrome?

Dr Bowen: Most of the time, no. There is little reason to wait, and in fact, operations are done sooner than the usual threshold in certain circumstances, such as an adverse family history.

Dr Gersh: Such as in pregnancy?

Dr Bowen: Yes, particularly, when there is rapid growth of the aorta.

Dr Gersh: So then you would do it when it reaches 4 to 4.5 cm?

Dr Bowen: Yes.

Dr Gersh: What else has contributed to the improvement in longevity?

Medical Therapy for Marfan Syndrome

Dr Bowen: Medical therapy is on the threshold of major improvements, we hope. For some time now, the medical therapy has been directed at the protection of the aorta.

Dr Gersh: Do you mean beta-blockers?

Dr Bowen: Beta-blockers are given to reduce hemodynamic stress, but also we use lifestyle changes. Patients with Marfan syndrome are taught that they should not do certain things, such as contact sports or extreme exertion. That is part of it. Beta-blockers have been and still are standard therapy. Of interest, the trials that have shown the benefit of beta-blockers involved relatively few patients, but they are still the standard treatment.

But now, because the fibrillin molecule, which is the cause of the Marfan syndrome, is a regulator of [transforming-growth factor]-TGF-beta signaling, now there is a brand new potential therapy, which is downregulation of TGF-beta signaling. This has been proven in laboratory animals in the mouse model. As we speak today, there are 10 trials going on around the world studying losartan in human beings, and we anticipate that some of these will be reported in the next year to two years.

Dr Gersh: This has really been a fascinating and striking example of a genetic model being translated to the clinical laboratory or the clinical setting, because it is an angiotensin-receptor blocker and it doesn't apply to an angiotensin-converting enzyme inhibitor. It's very specific.

Dr Bowen: Yes, at least in the mouse model, blockade of the angiotensin II type 1 (AT1) receptor seems to be very important.[4]

Dr Gersh: At this stage, should we be using losartan or an equivalent clinically, or should we be entering patients into trials? What should we do if we can't enter them into a trial?

Dr Bowen: The prudent thing to do, and what we do today, is to stay with the standard therapy, which is beta-blockade. Many patients have heard about losartan and request losartan, and particularly in patients with elevated blood pressure—after all, it is a standard antihypertensive—I feel comfortable adding losartan. After a discussion with the patient and informed consent, it's okay, but I don't feel comfortable using losartan alone just yet.

Dr Gersh: Just to wrap up, what can we look forward to in the next 10 years? It's been a pretty dramatic last 20 years, but what do you think is around the corner?

Dr Bowen: It has been very exciting, because for the first time there is the potential for treatments that affect the pathogenesis of the condition, and the basic science laboratories are busy around the world studying more than just dissecting the TGF-beta pathway. There will be new molecular targets, there will be specific molecular therapies, and we will find improved ways to assess the health of the aorta beyond just its diameter.

Dr Gersh: Thank you for joining us.

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