Monday, May 11, 2009

Thoracic Aortic Aneurysms and Stroke

Today I am writing to bring your attention to another gene found in Thoracic Aortic Aneurysm. There is a nice genetic review on the subject at

The problem with Aneurysms is that they are essentially ticking time bombs in the body often waiting to explode and ultimately kill you by bleeding in your brain, chest or belly. Kind of makes SNP scans look silly compared to the life and death issues here. In fact, sometimes armed with merely a family history you can find these people and save their lives.

Cardiovascular manifestations of familial thoracic aortic aneurysms and aortic dissections (TAAD) include: (1) dilatation of the aorta at the level of either the ascending aorta or the sinuses of Valsalva; and (2) aneurysms and dissections of the thoracic aorta involving either the ascending or descending aorta. Cardiovascular manifestations are usually the only findings. Affectedindividuals typically have progressive enlargement of the ascending aorta leading to either aortic dissection involving the ascending aorta (type A dissection) or consequent tear or rupture. The onset and rate of progression of aortic dilatation is highly variable.

TAAD is inherited in an autosomal dominant manner with variable expression and decreased penetrance. The majority of individuals diagnosed with familial TAAD have an affected parent. The children of an affected parent are at 50% risk of inheriting the mutant allele and the disorder. Prenatal testing may be available through laboratories offering custom prenatal testing.

I take care of a few patients like this and you may miss this condition, unless you take a good family history. It is often described as "Heart was torn" "Sudden Death" "Abdominal Aneurysm" or even "Heart Attack"

This is why I am all about getting your family history, but then reviewing it with a medical professional. Most of our patients come back, time and time again bringing new medical information. This helps us best treat and prevent disease. In the case of TAAD, if your sister or brother or mother or father had the syndrome, you are at 50-50 odds of having it too.

Since often the only signs and symptoms are chest pain and sudden death.......It helps to have a surveillance plan. But how do we diagnose these patients?

TAAD is diagnosed based on the presence of dilatation and/or dissection of the thoracic aorta, absence of Marfan syndrome and other connective tissue abnormalities, and presence of a positive family history. TGFBR2 (encoding transforming growth factor beta receptor type II), TGFBR1 (encoding transforming growth factor beta receptor type I), MYH11 (encoding myosin-11), ACTA2(encoding alpha 2 actin, aortic smooth muscle), and two loci, FAA1 and TAAD1, are known to be associated with TAAD. Further locus heterogeneity is evident. Molecular genetic testing for TGFBR1, TGFBR2,MYH11, and ACTA2 is available clinically. Molecular genetic testing for the other the loci are currently performed on a research basis only.

One of my families with this condition actually also has a strong family history of stroke. Traditionally, we thought that this TAAD didn't involve other vascular issues. We were once again, proven absolutely wrong.

Dianna M Milewicz, MD, PhD recently discovered in a familial cohort, relation between ACTA2 and TAAD with stroke.

"Mutations in Smooth Muscle Alpha-Actin (ACTA2) Cause Early Onset Coronary Artery Disease, Stroke and Moyamoya Disease, Along with Thoracic Aortic Aneurysms and Dissections," is published early online in the American Journal of Human Genetics.
This just goes to show that assumptions are often false, which is why most GWAS come back false in the end. Because assumptions about not having assumptions can lead us even further astray. With ACTA2 I wonder why we didn't think this smooth muscle gene was a candidate before.

So what do we do to defuse the ticking bomb?


Echocardiography should be performed at frequent intervals to monitor the status of the ascending aorta.

  • Yearly examinations are sufficient with relatively small aortic dimensions and slow rates of aortic dilatation.

  • More frequent examinations are indicated in any of the following situations:

    • The aortic root exceeds about 4.5 centimeters in adults.

    • The rate of aortic growth exceeds about 0.5 cm per year.

    • Significant aortic regurgitation occurs.

The entire aorta should be imaged every few years, as the incidence of aneurysms in other portions of the aorta may be as high as 20%.

After repair of the ascending aorta, the remaining portion of the aorta needs to be routinely imaged for enlargement of the distal aorta, whether the individual had a type A dissection initially or underwent prophylactic repair of the ascending aorta.

Periodic imaging of the cerebral circulation in individuals with a TGFBR2 mutation to evaluate for cerebral aneurysms is recommended as these aneurysms may occur later in life.

Hemodynamic stress. Medications that reduce hemodynamic stress, such as beta adrenergic blocking agents, are routinely prescribed for individuals with the Marfan syndrome, and similar treatment is recommended for individuals with familial TAAD [Shores et al 1994]. Aortic dissection is exceedingly rare in early childhood, but aortic dilatation may be present in childhood. Medical therapy should be considered in children and adults with aortic dilatation.

Hypertension should be aggressively treated and controlled in individuals with TAAD.

Prophylactic surgical repair of the aorta to prevent subsequent dissection or rupture is indicated in any of the following situations

  • When the rate of dilation approaches 1.0 cm per year

  • When aortic regurgitation progresses

  • For individuals with familial TAAD caused by TGFBR2 mutations before the diameter of the ascending aorta reaches 5.0 cm

  • For those with bicuspid aortic valve (BAV) when the diameter of the ascending aorta is 5.0 cm

  • For all others with TAAD, when the diameter of the ascending aorta is between 5.0 cm and 5.5 cm

More recently, a valve-sparing procedure has been developed that precludes the need for chronic anticoagulation [David et al 1999].

More aggressive surgical repair may be indicated for individuals with a family history of aortic dissection without significant aortic root enlargement and in individuals with TGFBR2 mutations.

You can see that this watchful waiting and action when indicated pathway is very similar to other things we do, including BRCA positive surveillance options. This is why genomic medicine will win in the end. We will catch those who have these horrible time bombs and help prevent them. In my mind that is a home run every time. Will testing take place before a good family history? Only if we don't have the skilled manpower to take good histories and physicals.......

The Sherpa Says: I just discovered another one of these families last week. I will say it again and again. You miss 100% of putts you leave short. I.E. if you don't look, you never find.


Ginna Dorkin said...

An aortic aneurysm is caused due to bulging of the aorta, the main artery in the body that passes blood from the heart to the rest of the body. If not treated in time the aorta may burst, serious bleeding may cause death. Know more consult here

DR Di LUOZZO said...

Just wanted to inform readers of your blog that Mount Sinai in New York City has the most sophisticated surveillance program for thoracic aortic aneurysms. We have been sponsoring a Aortic Symposium since 1990 which is attended by over 1500 physicians worldwide. Drs. Griepp and Di Luozzo have written extensively about aortic diseases throughout the years. The program investigates all patients for the possibility of familial thoracic aneurysm syndromes. Please visit the mount sinai website: or

Anonymous said...

When does the doctor opt for open heart surgery and when to do a stint for ascending aortic aneurysm?

DR Di LUOZZO said...

We had a wonderful lecture at Mount Sinai by Dr. Dietz on his work with Marfan and Loey-Dietz syndrome. He has a wonderfully thoughtful research team with interesting results. I think the reuslts of the losartan trial in Marfan patient should be promising. What do you think?