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Thoracic Aortic Aneurysms and Stroke

Posted May 12 2009 3:48pm

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 offamilialthoracic 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 anautosomal dominantmanner with variable expression and decreasedpenetrance. The majority of individuals diagnosed withfamilialTAAD have anaffectedparent. The children of anaffectedparent are at 50% risk of inheriting the mutantalleleand the disorder. Prenatal testing may be available through laboratories offeringcustom 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 positivefamily 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. Furtherlocus heterogeneityis evident.Molecular genetic testingfor TGFBR1, TGFBR2,MYH11, and ACTA2 is available clinically.Molecular genetic testingfor 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 MMilewicz, MD, PhDrecently discoveredin a familial cohort, relation betweenACTA2 andTAADwith 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 theAmerican 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?


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

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

  • More frequent examinationsare 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 imagedevery 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 circulationin individuals with a TGFBR2mutationto evaluate forcerebral 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 theMarfan syndrome, and similar treatment is recommended for individuals withfamilialTAAD [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 withfamilialTAAD 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 afamily historyof 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.

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