Matters of the heart – treating Marfan syndrome

Marfan syndrome (MFS) is a genetic disorder of the connective tissue caused by a mutation on FBN1, the gene coding for fibrillin-1. The mutation causes an increase in protein-transforming growth factor beta (TGF-β), which affects the production of the elastic fibres of the connective tissues. Approximately one in 5,000 people globally suffer from the disease, and it occurs equally in men and women. Rates are generally similar between most races and regions in the world, except for what appears to be a higher proportion of sufferers in the Middle East.

The disease is an autosomal dominant disorder, which means that parents have a 50% chance of passing the disease onto their children. Most of the time, it is inherited from the parent, although in 25% of cases, there is no family history of MFS, meaning it is caused by a new mutation. The disease presents differently in each person but sufferers tend to be tall and thin, with long limbs, flexible joints and a curvature of the spine. It can affect the lungs, eyes, bones and covering of the spinal cord. Other symptoms could include undue fatigue, shortness of breath, heart palpitations or a racing heartbeat, chest pain, and cold hands and feet.

The most serious complications, however, involve the heart, with 90% of sufferers having medical issues related to the organ and its blood vessels. The commonest cause of death among people with MFS is an ascending aortic dissection – a tear or rupture between the layers of the aortic walls – and is most often seen in young-adult life. Other common issues include aortic aneurysm, where the aorta grows to more than 1.5 times its normal size, causing the walls of the heart to bulge, and aortic regurgitation, where the valve does not close properly because the aorta is enlarged, and blood leaks back into the heart.

Sufferers of MFS also have an increased risk of mitral valve prolapse, the displacement of an abnormally thickened mitral-valve flap in the left atrium during systole. The flaps don’t close tightly enough, causing an irregular or rapid heartbeat and shortness of breath.

There is no cure; symptoms are treated as and when they arise, and preventative medicines such as beta blockers, calcium-channel blockers and ACE inhibitors are offered, even to young sufferers. Surgery is necessary if the dilation of the aorta progresses to a significant diameter, often with an aortic valve graft or valve-sparing aortic root replacement. These procedures are generally successful if undertaken on an elective basis.

Pioneering technique

An emerging technique offers a new way to manage the dilated aorta often seen in MFS patients. Personalised external aortic root support (PEARS) is a new approach to the surgical management of the dilated aorta. It uses a custom-made external support that exactly matches the patient’s aorta, turning the surgery into a more straight-forward procedure. PEARS uses spatial data from MRI or CT images, computer-aided design and 3D printing to create thermoplastic replica of the patient’s aorta.

“This is a bespoke sleeve of medically approved polyester mesh that has been heat-shrunk around a high-fidelity plastic model of the patient’s aortic root and ascending aorta,” explains Professor John Pepper, interim director of research, consultant cardiac surgeon and professor of cardiothoracic surgery at the Royal Brompton and Harefield Hospitals. “Computer-aided design [CAD] and rapid prototyping [RP] are used to build this from a digital image obtained from a high resolution CT scan of the patient’s aorta. Because of the CAD, it can be the same size as the aorta [100%] or slightly smaller, at 95 or 90%, but it is personalised to the patient – an example of precision medicine.”

In a paper published in the European Journal of Cardio-Thoracic Surgery in March 2016, surgeons using the technique – including Pepper and Professor Tom Treasure of the Clinical Operational Research Unit at University College London – have described the support as “intimately fitting hosiery; a soft stocking made to fit rather than being wrapped around the leg.”

The mesh is positioned around the part of the aorta most at risk, closely applied from the aorto-ventricular junction to beyond the brachiocephalic artery. It helps the aortic root maintain its shape and size over several years, and is likely to remain stable.

“It strengthens the aortic wall and should prevent either dissection or aortic rupture. The mesh material becomes incorporated into the outer wall of the aorta,” adds Pepper.

“The body’s repair mechanisms are triggered to grow into and around the mesh. The aorta and mesh become one reinforced structure,” says Treasure.

The mesh becomes united with the natural growth of adventitial collagen, and new blood vessels grow through and around the structure. This prevents it from moving independently of the aortic wall – a problem commonly seen with wraps and grafts. And because the mesh becomes incorporated into the aortic adventitia, it causes an overall increase – albeit a moderate one – in the thickness of the aorta.

The pre-emptive operation is designed to halt aortic root expansion and maintain aortic valve function, and can be carried out before the aorta expands to a size where root replacement is necessary.

“We will only use this procedure in patients whose aorta is moderately enlarged (40–50mm in diameter), and therefore early in the natural history of their disease,” states Pepper. “The patient still has the native aortic valve and the normal lining of the aortic wall, which we think is an advantage.”

The procedure spares the valve itself, conserving the architecture of the aortic valve support, and presents no obstacle to further surgery. During the surgery, there is no need to arrest the heart, nor to open the aorta, so coronary blood flow is uninterrupted. And since the technique is based on measurements taken from individual patients, risks of errors of judgement and technique are reduced.

Patient awareness

The first operation to use PEARS was conducted in 2004 by Pepper, and analysis of the first 20 patients several years later, compared with matched patients who underwent root replacement, showed that operation time was half that of the latter, blood loss a quarter, and transfusion and cardiopulmonary bypass was largely avoided. Evidence suggests that PEARS may offer equivalent protection to root replacement with lower early to late risk.

“The operation is much less destructive than standard methods: there is no need to stop the heart, the time of the operation and time in hospital can be halved, and the person can resume a normal life without the need for anticoagulants,” explains Treasure.

Authors of the European Journal of Cardio-Thoracic Surgery study hope to cautiously extend the use of PEARS with surgeons who wish to adopt the technique, potentially in the Middle East.

“More than 80 patients have had this surgery and increasing numbers are coming forward. Local surgeons used to operating on the aortic valve and the aorta can learn how to insert the mesh sleeve, which our team make to measure for the patient,” Treasure adds.

Just like the standard surgical procedures, PEARS cannot influence the course of MFS, or the likelihood of dilation or dissection beyond the limits of the support. However, the support routinely extends beyond the brachiocephalic artery and is more protective than the tube-graft component used in root-replacement operations.

“The main threat to patients with Marfan syndrome is the possibility of an aortic dissection or rupture, which, if untreated, leads to death,” says Pepper. “The most common site [95%] for this to occur is in the ascending aorta. By strengthening the aorta in this way, we believe we can prevent dissection without the need for either a valve replacement (Bentall operation) or a valve-sparing operation, which has a failure rate of 1–2% per year.”

Pepper believes that PEARS could become commonplace in the Middle East for treating MFS patients: “CT scanning is widespread. PEARS requires a special protocol for the CT that is quite straightforward for an experienced radiologist.”

The PEARS procedure was simulated at the 2016 Arab Health Expo in the Middle East by Ulrich Rosendahl, a cardiac surgeon at the Royal Brompton and Harefield Hospitals. The hope is that by raising awareness of the technique and training surgeons in the procedure, hospitals in the region will offer the treatment to patients over standard procedures. Rosendahl told the conference that PEARS is currently performed in the UK for patients from the Middle East, but that by visiting the region and educating healthcare providers, he hopes to bring the information and expertise to the area.

It is unclear why the disease appears to be more prevalent in the Middle East, although it has been suggested that it could be down to consanguinity. 20–50% of marriages in the area are between blood relations such as first cousins, meaning they share common ancestors and, therefore, the likelihood of passing on a genetic abnormality such as MFS is greater. Restrictive marriages to blocs or countries, and preventing marriage to anyone outside certain religions or sects may account for higher-than-average figures in the area.

In a region where MFS is seemingly more prevalent, PEARS has the potential to provide a pre-emptive solution to a deadly complication of the disease, and it is hoped that the procedure will replace the standard surgical aortic valve graft and valve-sparing aortic root replacement procedures in the Middle East. Not only will this allow sufferers to resume a normal life much sooner, thanks to shorter surgery and recovery times, but it could also lengthen their life expectancy and prevent the need for further surgery.