8 Aortopathies
Authors: Anna Ohlsson and Sherene Shalhub
Contributor: Wen Kawaji
8.1 General Considerations
What are the common genetic aortopathies?
There are several well-known genetic disorders which account for genetic aortopathies. The most well-known are Marfan syndrome, Loeys-Dietz Syndrome, and Vascular Ehlers-Danlos Syndrome.
There are less commonly known ones such as Familial Thoracic Aortic Aneurysms and Dissections due to pathogenic variants smooth muscle cells genes such as ACTA2. There are others in which the causative gene is not known.(Black 2019)
Why are they such a big deal?
These are cases in which the building blocks of the aortic wall are defective. What I mean by this, is that these patients have pathogenic variants in the genes that affect cell signaling or smooth muscle cell structure that lead to suboptimal composition of the aortic wall. These alterations ultimately lead to cystic medial necrosis in the aortic wall.
As such they are at more risk for aortic aneurysms and dissections that can lead to the premature death of the patient.
To put the frequency in perspective, Marfan syndrome occurs in 1:5000 of the population while Vascular Ehlers-Danlos syndrome (also known as VEDS) occur in 1:50000 of the population.
Let’s dive into them then – what are the defining features of each and the high yield information?
The high yield information is being able to pair the genetic syndrome and phenotype with its associated genetic mutation. A useful exercise following this broadcast is to list the disorders in a table and write out their associated gene mutation, what protein defect or deficit occurs, the typical phenotype, and the common vascular pathology associated.
But before we dive in, I want you to keep in mind some of shared features. One is that the associated aneurysms and dissections tend to occur at younger ages and dissect at lower blood pressures than what we see with sporadic dissections (these are the dissections that are not familial or associated with a syndrome)
One is that these are inherited in an autosomal dominant matter but there can be variation in how the pathogenic variants are expressed among affected people and even within families. The other thing to remember, is that in roughly half of these cases, the affected patient is the first in their family to have a given pathogenic mutation. The flip side of this, is in half the cases, there is a family history of aortic aneurysms, dissections, and sudden death.
8.2 Demographics
We will start with Marfan syndrome.
Marfan syndrome is caused by pathogenic variants in the FBN1 gene (also known as fibrillin-1 gene). These variants lead to improper formation of the microfibrils that maintain elastin, a key component of the arterial wall.
These patients are prone to aneurysmal degeneration and dissections of the aortic root but can also dissect the descending thoracic aorta. They commonly have lens dislocations (ectopia lentis). They have common skeletal features such as being tall, thin, with long arms and legs, scoliosis, pectus deformities (carnitatum or excavatum), and club feet. They can also have a history of spontaneous pneumothorax and mitral valve prolapse.
How is Marfan syndrome similar or different from the other genetically triggered aortopathies that you mentioned?
Loeys Dietz Syndrome is similar to Marfan syndrome in all the features including the aortic root aneurysms. They don’t seem to have lens dislocation and they have other unique features such as bifid uvula or cleft palate, and hypertelorism (which is an abnormally increased distance between the eyes). What is different about Loeys Dietz Syndrome from Marfan syndrome is that they can have arterial aneurysms of other arteries instead of the aorta, such as the SMA, axillary, or other peripheral arteries.
Vascular Ehlers-Danlos syndrome has some shared features to Marfan Syndrome with both such as spontaneous pneumothorax, but these patients tend to be short and can have easy bruising. They also have similar features to Loeys Dietz syndrome in terms of arterial aneurysms. Common features of VEDS would be thin translucent skin where you can easily see their veins, thin lips, thin bridge of the nose, large eyes, easy bruising, acrogeria – or an aged appearance of the hands
However, unlike Marfan and Loeys-Dietz, the majority of VEDS patients tend to not have aortic root aneurysms. One thing to remember about VEDS is that it is a subtype of Ehlers Danlos syndromes. It’s very important to distinguish it from the other subtypes because most of the other 12 Ehlers-Danlos syndromes are not associated with arterial pathology. So people with vascular EDS are prone to arterial, uterine, and intestinal rupture and their average lifespan is 48 due to these highly morbid pathologies. 25% of patients with vEDS will have experienced some clinical manifestation by age 20, and that number is close to 90% by age 40.
I remember learning about classic Ehlers-Danlos presenting with hypermobile skin and joints. Is this something you see with Vascular EDS as well?
Patient’s with vEDS don’t have the same hypermobile skin or joint laxity as we classically think of with classic Ehlers-Danlos. In fact, some vEDS patients report losing confidence in their physicians who ask them about joint and skin hypermobility because it suggests to them that their doctor doesn’t know about their disease process. These patients often know more than most of the doctors they meet about their condition, and it’s a source of constant frustration for them. It can also be a problem if the severity of the disease is underestimated, as we discussed they can present much younger than most patients with highly morbid issues – like arterial rupture.
You mentioned arterial pathology in Loeys-Dietz and vEDS. Can you tell me more about that?
In both types you can see subclavian, carotid, SMA, and iliac artery aneurysms and dissections, as well as less frequently vertebral, SFA, and popliteal aneurysms and dissections.
8.3 Evaluation
How do you diagnose these genetically triggered aortopathies?
There are clinical diagnostic criteria for each, but ultimately genetic and laboratory testing is very important for the final diagnosis.
Ghent criteria is used to clinically diagnose Marfan syndrome. The big ones are aortic root dilation, known family history of Marfan’s or not, the diagnosis of ectopia lentis which clinically is manifested as iridodonesis (lens shimmering). Additionally, genetic testing for pathogenic FBN1 variants is also diagnostic.
To date, there are 5 types of Loeys-Dietz as of last check. These are due to pathogenic variants in the TGF-B signaling pathway, such as TGF-beta receptors and SMAD3 genes.
Vascular EDS is caused by a mutation in the COL3A1 gene which encodes a defective type of III procollagen. The defect in the procollagen makes it unable to properly fold into a triple helix that forms the normal collagen structure. This causes the defective procollagen to be degraded intracellularly and as a result there is an overall deficit in type III collagen which is an important component of arterial walls and other structures. The confirmatory test for VEDS is collagen testing which can confirm the collagen III defect.
8.4 Management
8.4.1 Medical Management
How would you manage these patients?
Medical optimization and surveillance is key to try to extend the time as much as possible before they get a dissection and avoid it if at all possible.
We start with lifestyle modification. Avoid “burst” exertions such as sprinting and weight-lifting. Anything that very strenuous. That’s not to say that they shouldn’t exercise. Light exercise is encouraged, but this would be activities like light jogging, swimming laps, or biking.
In order to minimize aortic shear stress, a resting heart rate of under 70 beats per minute and an exercising heart rate under 100 should be the goal. This can be accomplished with beta blockers. Propranolol has been shown to significantly decrease the rate of aortic growth in Marfans patients with a baseline aortic root diameter under 4cm. There is research into the use of Losartan in murine models that suggests it inhibits TGF-beta in the aortic wall, which is an important pathway that contributes to the breakdown of the wall. However, randomized controlled studies have failed to show an increased benefit of Losartan over beta blockers in Marfans patients. ACE inhibitors are also being tested and are shown to decrease the risk of type b aortic dissection over 6 years.
In vascular EDS instead of propranolol, celiprolol has been studied by the French and shown to reduce vascular rupture from 50 down to 20% in vEDS, although the mechanism of this is not yet clear and does not appear to be necessarily the same as decreasing shear stress as in Marfan’s syndrome.(Ong et al. 2010) In general taking care of these patients involves trying to minimize complications from procedures and interventions. For instance, use ultrasound for any line that is necessary and avoid arterial lines, intramuscular injections, or other invasive lines if possible to minimize the chance of a complication. Patients are advised to wear medical bracelets notifying that they have vEDS.
We also discuss the importance of forming a care team based on their needs. This usually includes a cardiologist, a cardiac surgeon, a vascular surgeon, and a primary care physician.
8.4.2 Surgery
What about surgical treatment for those who need it?
For patients with Marfan’s, prophylactic surgery is recommended for aortic root dilation >5cm or thoracic aorta >5.5cm. Often times the thoracic and abdominal aorta are involved. Open and endovascular surgery are options for these patients. Open procedures often include open thoracoabdominal aortic aneurysm repairs, open cardiac surgery for arch replacement, or cervical debranching procedures. Endovascular procedures can include regular TEVARs or branched TEVARs which require extensive aortic coverage.
Open surgery can be well tolerated and is ideal in the sense that you can replace the entire aorta which avoids the future complications from continued aneurysmal degeneration, loss of proximal or distal seal zones, or device issues that can plague endovascular methods. However open surgery, of course caries higher complication risk and morbidity up front and does share some complications with endovascular treatments as well.
Sometimes these patients will have hybrid procedures and often their care will require multiple surgery teams including cardiac and vascular surgery. An important thing to be up front with all of these patients about is that this is a long term relationship with their surgeon, as they often require multiple staged procedures, things aren’t fixed in one procedure, and even after they have been surgically addressed there is a lifetime of maintenance and surveillance.
Ultimately, the decision for open vs. endovascular approaches will vary between patients based on their specific anatomy and arterial issues, what their body can tolerate, and ultimately what their goals of care are.(Lum et al. 2012) Some may require having their entire aorta replaced, while others may only need ongoing medical therapy and surveillance and it’s important to set expectations early.
What about VEDS, when surgery cannot be avoided? How do you mitigate the risk of complications?
The tissue is very fragile. So using instruments that are the least traumatic is key – like fogarty clamps for vessels. Sutures often must be pledgeted to reinforce them. Leave no tension on anastomoses or suture lines. Always keep a backup plan in mind– when arteries cannot be repaired, can they safely be ligated or embolized. Generally any large bore access for endovascular treatment is avoided because access site complications are high and can lead to devastating consequences. Some have described a technique of open exposure and buttressed repair, when endovascular approaches are required.(Black 2019)
In situations of extremis, like a rupture, these patients’ tissues have been known to completely breakdown. This is often their first presentation of their aortopathy so there is no time for previously discussed work up or considerations. Try to avoid the worst case scenario, but of course sometimes it’s the only option left to get out of the OR. Be upfront with the patient about how complications may arise, set expectations, and think about goals of care early.
Some specific considerations for TEVAR in these patients is that it may be important to have cardiac surgery readily available because they are high risk for retrograde dissection. Also, avoid aggressive oversizing, consider not ballooning if no leak is identified and avoid excessive wire manipulation.
8.5 Summary
We discussed earlier that these aortopathies can have shared phenotypic characteristics, some of which can be used in a clinical diagnosis, but are all of these genetic aortopathies syndromic?
Let’s start by saying that all patients with Marfan syndrome and VEDS can have the syndromic features we just talked about. However, it’s not always the case and the absence of these feature does not exclude the diagnosis. In fact, we recently treated a middle-aged woman with an aortic dissection who had Marfan Syndrome confirmed with genetic testing. She had been diagnosed prior to her dissection because her daughter had undergone genetic testing. However, on meeting her, I would not have guessed she had Marfan Syndrome, had I not known. She was average height, obese, and had no other relevant physical findings on exam or history.
This ties into another genetic aortopathy that we have not discussed yet which are the familial thoracic aortic aneurysms and dissections. They do not have any syndromic features. For example, patients with ACTA2 pathogenic variants that cause alpha actin mutations which again contribute to degeneration of the arterial wall. These patients tend to present 10 years younger than sporadic thoracic aortic aneurysms, generally in their late 50s compared to late 60s, and women seem to be less often effected than men.
Dr. Shalhub, I know vascular genetics is one of your passions. Is there anything else you want people to remember from this broadcast?
Don’t forget the family. Once you’ve made the diagnosis in one of them, remember it is autosomal dominant, so it’s important to make sure the family understands and that they are set up with the appropriate care team and monitoring. They may not all develop the same medical issues, however as we discussed, ongoing medical management and lifestyle changes are the key.
8.6 Additional Resources
VEDS Research Collaborative study: