Introduction

The importance of Marfan studies:

Marfan syndrome is one of the most common inherited disorders of connective tissue with a high
rate of occurrence worldwide, once in every 10,000 to 20,000 individuals. Patients with Marfan
may suffer a wide variety of signs and symptoms.

Why I chose this theme:

My interest in this disease is due that Marfan syndrome result a complex disease with an important
inheritance factor. In addition, this affection has a multivariate signs and symptoms, this makes this
condition difficult to diagnose and management. Moreover, in the cardiovascular field, has made
great progress in elucidating the pathologies of this syndrome, and identifying potential new
therapies.

The structure of this presentation is a following:

Definition of the Marfan syndrome
Most relevant clinical manifestations
One example of one of the major importance research subjects in Marfan disorder
Conclusions

Definition
Marfan Syndrome is an inherited disorder that affects connective tissue (the fibers that support and
anchor your organs and other structures in your body), caused by mutation of the FBN1 gene, which
encodes fibrillin-1, a extracellular matrix protein that provides stretch and elasticity to connective
tissues. Most commonly affects the heart, blood vessels, eyes and skeleton.

People with Marfan syndrome are usually tall and thin whit disproportionately long arms, legs,
finger and toes. The damage caused by Marfan syndrome can be mild or severe. If the aorta (the
largest blood vessel that carries blood from your heart to the rest of your body) is affected, the
condition can become life-threatening.

Epidemiology
Estimates indicate about 1 in 5,000 to 10,000 individuals have Marfan syndrome. It affects men and
women equally and occurs among all races and ethnic groups. However, women with Marfan
syndrome live longer than men.

Because it's a genetic condition, the greatest risk factor for MFS is having a parent with the
disorder. Most people with Marfan syndrome inherit the abnormal gene from a parent who has the
disorder. Each child of an affected parent has a 50-50 chance of inheriting the defective gene.

In about 25% of the people who have Marfan syndrome, the abnormal gene doesn't come from
either parent. In these cases, a new mutation develops spontaneous.

History
Marfan syndrome is named after Antonie Marfan, the French pediatrician who first described the
condition in 1896 after noticing striking in a five-year-old girl. The gene linked to the disease was
first identified by Francesco Ramirez at the Mount Sinai Medical Center in New York City in 1991.

Signs and symptoms

Because Marfan Syndrome can affect almost any part of your body, it may cause wide variety of
signs and symptoms. The most common are:
Cardiovascular:
The most dangerous signs and symptoms associated with Marfan syndrome involve the heart and
blood vessels. Faulty connective tissue can weaken the aorta. Cardiovascular complications may
include:

• Aortic aneurysm: The pressure of the blood leaving your heart can cause the wall of your aorta to
bulge out; this is most likely to happen at the aortic root.

• Aortic dissection: The wall of the aorta is made up of layers. Dissection occurs when a small tear
in the innermost layer of the aorta’s wall allows blood to squeeze in between the inner and the
outer layers of the wall. This can cause severe pain in the chest or back. An aortic dissection
weakens the vessel’s structure and can result in a rupture, which may be fatal.

• Valve malformations: People who have Marfan Syndrome also are more likely to have problems
with their heart valves, which may be malformed or overly elastic. When heart valves don’t work
properly, your heart often has to work harder to compensate. This can eventually lead to a heart
failure

Eye:
In Marfan syndrome, the health of the eyes can be affected in many ways, the most common are:

• Lens dislocation: The focusing lens within your ayes can move out of place if its supporting
structures weaken. The medical term of this problem is ectopia lentis, and it occurs in more than
half of people who have Marfan syndrome

• Retinal problems: Marfan syndrome also increase the risk of a detachment or tear in the retina, the
light-sensitive tissue that lines the back wall of your eye.

• Early-onset glaucoma or cataracts: People who have Marfan syndrome tend to develop these eye
problems at young age. Glaucoma causes the pressure within the eye to increase, which can
damage the optic nerve. Cataracts are cloudy areas in the eye’s normally clear lens.

Skeletal:
Most of the readily visible signs are associated with the skeletal system. Many individuals with
Marfan syndrome grow above the average height, and some have disproportionately long, slender
limbs with thin, weak wrists and long fingers and toes. Besides affecting height and limb
proportions, people with Marfan Syndrome may have abnormal lateral curvature of the spine
(scoliosis).

Treatment and management

There is no cure for Marfan syndrome, but life expectancy has increased significantly over the last
few decades and is now similar to that of the average person. Regular checkups are recommended
to monitor the health of the heart valves and the aorta. MFS is treated by addressing each issue as it
arises and, in particular, preventive medication even for young children to slow progression of
aortic dilation. The goal of this treatment strategy is to slow the progression of aortic dilation and
prevent any damage to heart valves by eliminating heart arrhythmias, minimizing the heart rate, and
lowering the person's blood pressure.

Physical activity:
The American Heart Association made the following recommendations for Marfan’s pattens with
no mild aortic dilation: Bowling, golf, stationary biking and doubles tennis.

Medication:
Management often includes the use of beta blockers such as propranolol or if not tolerated calcium
channel blockers or ACE inhibitors.

Surgery:
If the dilation of the aorta progresses to a significant diameter aneurysm, causes a dissection or a
rupture, or leads to failure of the aortic or other valve, then surgery becomes necessary. The surgery
could be a composite aortic valve graft or valve-sparing aortic root replacement, however each case
needs to be specifically evaluated by a qualified cardiologist.

Because Marfan syndrome causes asymptomatic spinal abnormalities, any spinal surgery
contemplated on a person with Marfan should only followed detailed imaging and careful surgical
planning, regardless of the indication of surgery. On the other hand, if the eyes are affected, any
necessary surgery will be performed by the specialist.

Even though there are a lot of treatments, cardiovascular symptoms of Marfan syndrome are still the
most significant issues in diagnosis and management of the disease, even some people requires
more than one surgery to live. But adequate prophylactic monitoring and prophylactic therapy
offers something approaching a normal lifespan.

Investigation
Groenink, M., Den Hartog, A. W., Franken, R., Radonic, T., De Waard, V., Timmermans, J., et al. (2013).
Losartan reduces aortic dilatation rate in adults with Marfan syndrome: a randomized controlled
trial. European Heart Journal, 34(45), 3491–3500. https://doi.org/10.1093/eurheartj/eht334
Aim:
The primary aim of the study was to determine whether losartan reduces the aortic dilatation rate in
adults with MFS.

Method:
The study was a randomized, multicentre, open-label trial with blinded assessments of selected
endpoints.
The sample was selected from January 2008 until December 2009. Thus 233 patients (38+13 years,
47% females) were enrolled, of which, 116 were treated with losartan and 117 that did not receive
treatment. All of them were follow-up by 3.1+0.4 years.
The selected endpoints to evaluate were: (i) aortic dilatation rate at the six predefined aortic levels,
(ii) total aortic volume expansion rate, (iii) the incidence of: cardiovascular mortality, aortic
dissection, or prophylactic aortic surgery

Results:
Aortic root dilatation rate was evaluated in 145 patients with a native aortic root at the time of
exclusion. The aortic root dilatation rate was significantly lower in the losartan group than in the
control group, 0.77+1.36 vs. 1.35+1.55 mm/3 years, respectively.

The aortic volume increase was assessed in 168 MFS patients with a native aortic root or aortic root
replacement prior to study inclusion. In these cases, no difference in clinical endpoints was found.
In 63 patients, who had an aortic root replacement surgery prior to this study (27 in the losartan
group). After aortic root replacement, aortic arch dilatation rate was significantly lower in the
losartan group than in the control group.

Aortic dilatation rate in the descending aorta at the level of the pulmonary artery and diaphragm
was comparable between the groups. No significant difference in aortic volume increase between
groups could be demonstrated.

Following a correlation analysis, the change in the mean arterial blood pressure or change in
systolic blood pressure was not correlated with aortic root dilatation rate in patients treated with
losartan or controls.

Discussion and conclusions:

The researchers observed a reduction of mean aortic root dilatation rate in the losartan group,
irrespective of age, sex, blood pressure, aortic root size.

This study has shown that losartan was significantly associated with reduced dilatation rate of the
aortic arch in patients with aortic surgery. However, this result should be interpreted with some
caution because the aortic dimensions of patients with prior aortic root replacement were not
completely comparable with control group.

No correlation was found between change in the mean arterial pressure or systolic blood pressure
with aortic root dilatation rate.

The overall effect of the losartan treatment in patients with MFS, has a beneficial effect on aortic
dilatation.

Conclusions
The investigation and management of patients with Marfan syndrome is complex and requires a
multidisciplinary approach. Over the past four decades, remarkable progress in understanding the
cause, pathogenesis, and management of the MFS has led to an increase in life-expectancy to near
normal for most patients. Despite improvements of medical and surgical management for MFS,
cardiac morbidity remains a major concern among researchers.

One of the most exciting advance in the study of Marfan’s syndrome in recent years has been the
appreciation that Losartan, an angiotensin II type 1 receptor blocker used in the treatment of
hypertension and heart failure, has a important beneficial effect on the cardiac manifestations.

References
Ammash, N. M., Sundt, T. M., & Connolly, H. M. (2008). Marfan Syndrome Diagnosis and Management.
Current Problems in Cardiology, 33(1), 7–39. https://doi.org/10.1016/j.cpcardiol.2007.10.001

Groenink, M., Den Hartog, A. W., Franken, R., Radonic, T., De Waard, V., Timmermans, J., et al. (2013).
Losartan reduces aortic dilatation rate in adults with Marfan syndrome: a randomized controlled
trial. European Heart Journal, 34(45), 3491–3500. https://doi.org/10.1093/eurheartj/eht334

Loeys, B. L., Dietz, H. C., Braverman, A. C., Callewaert, B. L., De Backer, J., Devereux, R. B., et al.
(2010). The revised Ghent nosology for the Marfan syndrome. Journal of Medical Genetics,
47(7), 476–485. https://doi.org/10.1136/jmg.2009.072785