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 GeneTests.org

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?

Surveillance

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.

DTC Genomic tests? Who's that?

The American College of Physicians is perhaps getting the act together.....

Recently I sent an article to the ACP President Jeffrey Harris, I scolded him about how short sighted it was not to include topics on Genetics at the ACP conference in April. I still have received no response back from him......

BUT......

It appears the ACP is looking for Internists who have experiences with DTC Genomic testing.

Your thoughts exactly: direct-to-consumer genetic tests

ACP Internist is assessing how often internists are asked by patients about direct-to-consumer genetic tests.

Tell us about your experiences.
Learn more about the impact of direct-to-consumer genetic tests here and here.

They link to an article from Greg Feero. In which he says:

"This amounts to DTC marketing of the genetic equivalent of a full-body CT scan"

Is that what MDVIP is doing? Now imagine them doing the full body CT without a radiologists interpretation........ That is exactly what MDVIP is doing......

This is the image of DTC which will now be painted in the Internal Medicine Doctor's mind. Too bad that they will apply this image to ALL genetic testing :(

The Sherpa Says: ACP, you may be coming around.....but a 3 question Survey Monkey effort is hardly what I call real effort....

Experimental Man Debuts!!!

I am so happy to know David Ewing Duncan. Aside from him appearing on one of the CliniCasts last year (The day former president G.W. Bush signed GINA into law) he is a great writer and has been in the thick of the San Francisco Genome Scan Craze.

David has been talking about gaining greater insight into one's health for quite a while now.....

Finally he takes the time and puts his adventure into a book and a website.

The Book, Experimental Man is already on sale at Amazon! He debuts this book next week in New York City. I will be at his book signing and wish I was at his Today Show interview!!!

What is the Experimental Man? Well a brief read of this excerpt will give you some insight.

David has been doing all sorts of experiments on himself. From Exposing himself to Mercury and Surviving (Take That, Jeremy Piven.) to Functional MRIs, consumer and academic genome scans. David serves himself up as an investigator. This allows you to become a voyeur of self exploration.......

David's Website is a rich resource for information. From Leo Trasande, a guy who was a fellow while I did my internship under him at Mount Sinai to finding out your Brain Age.......

If you haven't thought about what the ramifications of finding out about your genome are, David is a great test subject.......and a pretty good blogger.

If you have time to read a book, this should be one of your first books in the personalized medicine space....

The Sherpa Says: David, Congratulations. Your book will be a very useful resource for the masses who want to learn more about themselves....and you.

BRCA Webcast Sherpas Repost

I vowed I would never post when family took precedence. I have to break that vow again today. I wish I didn't but there is something so vitally important that I must share with you. Why is this important? Because it might save more lives than have been previously lost.

The scourge of Ovarian and Breast cancer has ravaged several populations. With very few cases of early detection in Ovarian cancer, many women present with spread of the cancer and very poor prognosis. Even more importantly, women who have ovarian cancer and BRCA mutations still are at risk for other cancers including breast cancer. Despite this I have heard comments from Oncologists like "Why do we need testing?" This is why I have pulled myself away from my grief stricken family.

To fight this lack of knowledge I have dedicated and arm of Helix Health of Connecticut to educate and promote genomic medicine. This arm will host at minimum monthly podcasts on very important topics. The first of these is Hereditary Breast and Ovarian Cancers and the BRCA genes. The panel will include a patient with BRCA1. She not only happens to be afflicted, she has written about her experiences. Jessica is gifted with the pen and is a very successful writer. Her book "Pretty is What Changes" raises significant issues and serves as a wake up call to clinicians and patients. It serves to empower us all.

Jessica will join David Ewing Duncan, bestselling author of Masterminds: Genius, DNA and the Quest to Rewrite Life, and a panel of distinguished medical and legal professionals to discuss how the doctor-patient relationship is changing and what the potential liability is for physicians in this new era of breast & ovarian cancer and genomic medicine.

The Sherpa Says: The Helix Health of Connecticut webcast series is dedicated to my grandmother who died at 35 years of age from metastatic breast cancer. Too young for me to ever know. Please sign up for this conference. The information may just save a life......If Helix Health of Connecticut can save just one life then all the hard work is worth it. Please sign up now. Seats are limited, but you can also sign up for the podcast.