Aortic dissection pathophysiology: Difference between revisions

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[[Image:AoDissect Schema 01a.png|right|thumb|Blood penetrates the ''intima'' and enters the ''media'' layer.]]
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{{CMG}}; {{AE}} {{CZ}} {{Sahar}}


{{CMG}} ; {{AE}} {{CZ}}
==Overview==
[[Aortic]] dissection begins as a tear in the [[aortic]] wall in > 95% of patients. The tear is usually transverse, extends through the [[intima]] and halfway through the [[tunica media|media]] and involves ~50% of the [[aortic]] circumference. Two thirds of dissections originate in the [[ascending aorta]], and 20% are in the [[proximal]] [[descending aorta]].
==Pathophysiology==
===Normal Anatomy of the Aorta===
As with all other [[artery|arteries]], the [[aorta]] is made up of three layers. The layer that is in direct contact with the flow of blood is the [[tunica intima]], commonly called the [[intima]]. This layer is made up of mainly [[endothelial cell]]s. Just deep to this layer is the [[tunica media]], known as the [[tunica media|media]]. This middle layer is made up of [[smooth muscle]] cells and [[elastic tissue]]. The outermost layer (furthest from the flow of blood) is known as the [[tunica adventitia]] or the [[adventitia]]. This layer is composed of [[connective tissue]].[[Image:AoDissect Schema 01a.png|left|thumb|Blood penetrates the [[intima]] and enters the [[tunica media|media]] layer.]]
 
===Pathogenesis===
====Initial Intimal Tear====


==Overview==
* [[Aortic]] dissection begins as a tear in the [[aortic]] wall in > 95% of patients.
*It is usually transverse, extends through the [[intima]] and halfway through the [[tunica media|media]] and involves ~50% of the [[aortic]] circumference.
 
====Location of Dissections====
 
:*The initial tear is usually within 100 mm of the [[aortic valve]].
:*65% of dissections originate in the [[ascending aorta]], distal to the [[aortic valve]] and [[coronary]] [[ostium|ostia]]
:*10% arise in the [[transverse aortic arch]]
:*20% in the [[proximal]] [[descending aorta]]
:*5% in the more [[distal]] [[descending aorta]]


==Anatomy==
====Propagation of the Intimal Tear====
As with all other [[artery|arteries]], the [[aorta]] is made up of three layers.  The layer that is in direct contact with the flow of blood is the ''[[tunica intima]]'', commonly called the ''intima''.  This layer is made up of mainly [[endothelial cell]]s.  Just deep to this layer is the ''[[tunica media]]'', known as the ''media''.  This "middle layer" is made up of [[smooth muscle]] cells and elastic tissue.  The outermost layer (furthest from the flow of blood) is known as the ''[[tunica adventitia]]'' or the ''adventitia''. This layer is composed of [[connective tissue]].
In an [[aortic]] dissection, blood penetrates the ''[[intima]]'' and enters the ''[[tunica media|media]]'' layer. The high pressure rips the [[biological tissue|tissue]] of the ''[[tunica media|media]]'' apart, allowing more blood to enter. This can propagate along the length of the aorta for a variable distance, dissecting either towards or away from the [[heart]] or both.


==Pathophysiology==
Once a tear develops, blood then passes into the [[tunica media|media]], and a [[false lumen]] is dissected in the outer layer of [[aortic]] [[tunica media|media]] involving ~50% of the [[aortic]] circumference. This [[false lumen]] can enlarge, and compress the true [[lumen]], as well as extend [[proximal]]ly or [[distal]]ly and occlude [[aortic]] branches. For some unknown reason, the right [[lateral]] wall of the [[ascending aorta]] is the most common site for dissection. The [[right coronary artery]] can become occluded as a result of this propagation.
In an aortic dissection, blood penetrates the ''intima'' and enters the ''media'' layer. The high pressure rips the [[biological tissue|tissue]] of the ''media'' apart, allowing more blood to enter. This can propagate along the length of the aorta for a variable distance, dissecting either towards or away from the [[heart]] or both. The initial tear is usually within 100 mm of the [[aortic valve]].


The initiating event in an aortic dissection is a tear in the intimal lining of the [[aorta]].  Due to the high [[blood pressure|pressures]] in the aorta, blood enters the media at the point of the tear.  The force of the blood entering the media causes the tear to extend.  It may extend proximally (closer to the heart) or distally (away from the heart) or both.  The blood will travel through the media, creating a ''false lumen'' (the ''true lumen'' is the normal conduit of blood in the aorta).  Separating the false lumen from the true lumen is a layer of intimal tissue. This tissue is known as the '''intimal flap'''.
Separating the [[false lumen]] from the true [[lumen]] is a layer of [[intima]]l [[tissue]]. This [[tissue]] is known as the ''[[intima]]l flap''. As blood flows down the [[false lumen]], it may cause secondary tears in the [[intima]]. Through these secondary tears, the blood can re-enter the true [[lumen]].


==Origin of the Tear in the Aorta==
====Aortic Dissection in the Absence of an Intimal Tear====
The vast majority of aortic dissections originate with an intimal tear in either the [[ascending aorta]] (65%), the [[aortic arch]] (10%), or just distal to the [[ligamentum arteriosum]] in the [[Descending aorta|descending thoracic aorta]] (20%).
In about 13% of [[aortic]] dissections, there is no evidence of an [[intima]]l tear. It is believed that in these cases the inciting event is an intramural [[hematoma]] (caused by [[hemorrhage]] within the [[tunica media|media]]). Since there is no direct connection between the true [[lumen]] and the [[false lumen]] in these cases, it is difficult to diagnose an [[aortic]] dissection by [[aortography]] if the [[etiology]] is an intramural [[hematoma]]. An [[aortic]] dissection secondary to an intramural [[hematoma]] should be treated the same as one caused by an [[intimal]] tear.


As blood flows down the false lumen, it may cause secondary tears in the intima. Through these secondary tears, the blood can re-enter the true lumen.
An [[aortic]] intramural [[hematoma]] can form when the [[vasa vasorum]] ruptures into the [[aortic]] wall. This is distinguished from dissection by the lack of an [[intima]]l tear. This disorder parallels [[aortic]] dissection in terms of [[prognosis]] when the [[ascending aorta]] or [[aortic arch]] is involved, and rapid [[surgery|surgical]] intervention is indicated. Involvement of the [[descending aorta]], however, carries a better [[prognosis]] than dissection, and outcome tends to be similar with medical or [[surgery|surgical]] [[therapy]].


==Risk Factors for an Intimal Tear==
==Genetics==
While it is not always clear why an intimal tear may occur, quite often it involves degeneration of the [[collagen]] and [[elastin]] that make up the media.  This is known as ''[[cystic medial necrosis]]'' and is most commonly associated with [[Marfan syndrome]] and is also associated with [[Ehlers-Danlos syndrome]].  [[Aging]], [[atherosclerosis]], [[diabetes]], [[hypertension]] and [[trauma]] are common risk factors for aortic dissection. Uncommon risk factors include [[Bicuspid aortic valve]], [[cocaine]], [[Coarctation of the aorta]], [[Cystic medial necrosis]], [[Ehlers-Danlos syndrome]], [[Giant cell arteritis]], [[Heart surgery]], [[Marfan’s syndrome]], [[Pseudoxanthoma elasticum]], [[Turner's syndrome]], [[Tertiary syphilis]] and the [[third trimester of pregnancy]].
[[Genes]] involved in the [[pathogenesis]] of aortic dissection include:<ref name="PinardJones2019">{{cite journal|last1=Pinard|first1=Amélie|last2=Jones|first2=Gregory T.|last3=Milewicz|first3=Dianna M.|title=Genetics of Thoracic and Abdominal Aortic Diseases|journal=Circulation Research|volume=124|issue=4|year=2019|pages=588–606|issn=0009-7330|doi=10.1161/CIRCRESAHA.118.312436}}</ref><ref name="VerhagenKempers2018">{{cite journal|last1=Verhagen|first1=Judith M.A.|last2=Kempers|first2=Marlies|last3=Cozijnsen|first3=Luc|last4=Bouma|first4=Berto J.|last5=Duijnhouwer|first5=Anthonie L.|last6=Post|first6=Jan G.|last7=Hilhorst-Hofstee|first7=Yvonne|last8=Bekkers|first8=Sebastiaan C.A.M.|last9=Kerstjens-Frederikse|first9=Wilhelmina S.|last10=van Brakel|first10=Thomas J.|last11=Lambermon|first11=Eric|last12=Wessels|first12=Marja W.|last13=Loeys|first13=Bart L.|last14=Roos-Hesselink|first14=Jolien W.|last15=van de Laar|first15=Ingrid M.B.H.|title=Expert consensus recommendations on the cardiogenetic care for patients with thoracic aortic disease and their first-degree relatives|journal=International Journal of Cardiology|volume=258|year=2018|pages=243–248|issn=01675273|doi=10.1016/j.ijcard.2018.01.145}}</ref>
*[[FBN1]] ([[fibrillin-1]])
*[[Lysyl oxidase|LOX]] ([[lysyl oxidase]])
*[[MYH11]] (smooth muscle myosin heavy chain 11)
*[[ACTA2]] (smooth muscle α-actin 2)
*[[MYLK]] (myosin light chain kinase)
*[[PRKG1]] (protein kinase cGMP-dependent type 1)
*[[COL3A1]] (α-1 procollagen, type III)
*[[TGFBR1]] (TGF-β receptor type I)
*[[TGFBR2]] (TGF-β receptor type II)
*TGFB2
*[[SMAD3]] (mothers against decapentaplegic drosophila homolog 3)
==Associated Conditions==
[[Conditions]] associated with aortic dissection include:<ref name="PinardJones2019">{{cite journal|last1=Pinard|first1=Amélie|last2=Jones|first2=Gregory T.|last3=Milewicz|first3=Dianna M.|title=Genetics of Thoracic and Abdominal Aortic Diseases|journal=Circulation Research|volume=124|issue=4|year=2019|pages=588–606|issn=0009-7330|doi=10.1161/CIRCRESAHA.118.312436}}</ref>
*[[Aortic aneurysm]]
*Smooth muscle dysfunction syndrome
*[[Marfan syndrome]]
*[[Vascular Ehlers-Danlos syndrome]]
*[[Loeys-Dietz syndrome|Loeys-Dietz syndromes]]
==Gross Pathology==
[http://www.peir.net Images shown below are courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology]
<div align="left">
<gallery heights="225" widths="225">
Image:Aortic dissection 1.jpg|Dissecting [[Aneurysm]]: Gross fixed tissue external view of heart [[aortic arch]] and [[descending aorta]] showing dilated first and second portion of arch from [[anterior]] projection.
Image:Aortic aneurysm 8.jpg|Dissecting [[Aneurysm]]: Gross, a very good example of dissection beginning just above [[aortic]] ring.
Image:Aortic aneurysm 24.jpg|Dissecting [[Aneurysm]]: Gross dissection first portion of arch fixed [[specimen]] (a good example).
</gallery>
</div>
<div align="left">
<gallery heights="175" widths="175">
Image:Aortic aneurysm 1.jpg|Dissecting [[Aneurysm]]: Gross very good example dissected channel has been opened.
Image:Aortic aneurysm 2.jpg|Dissecting [[Aneurysm]]: Gross external view good appearance from [[adventitia]].
Image:Aortic aneurysm 3.jpg|Dissecting [[Aneurysm]]: Gross opened false channel.
</gallery>
</div>


==Aortic Dissection in the Absence of an Intimal Tear==
<div align="left">
In about 13% of aortic dissections, there is no evidence of an intimal tear. It is believed that in these cases the inciting event is an intramural [[hematoma]] (caused by [[hemorrhage]] within the media). Since there is no direct connection between the true lumen and the false lumen in these cases, it is difficult to diagnose an aortic dissection by [[aortography]] if the [[etiology]] is an intramural hematoma.  An aortic dissection secondary to an intramural hematoma should be treated the same as one caused by an intimal tear.
<gallery heights="175" widths="175">
Image:Aortic aneurysm 4.jpg|Dissecting [[Aneurysm]]: Gross good example dissection beginning at third portion [[aortic arch]].
Image:Aortic aneurysm 5.jpg|Dissecting [[Aneurysm]]: Gross cross sections showing [[thrombus]] in [[false lumen]]. True [[lumen]] has been opened longitudinally.
Image:Aortic aneurysm 6.jpg|Dissecting [[Aneurysm]]: Gross shows origin just above [[aortic valve]] false channel shown in [[descending aorta|descending]] [[thoracic aorta]] (very good example).
</gallery>
</div>


* Aortic dissection begins as a tear in the aortic wall in > 95% of patients. It is usually transverse, extends through the intima and halfway through the media and involves ~50% of the aortic circumference. 
<div align="left">
* Location of dissections:
<gallery heights="175" widths="175">
:*65% of dissections originate in the ascending aorta, distal to the aortic valve and coronary ostia.
Image:Aortic aneurysm 10.jpg|Dissecting [[Aneurysm]]: Gross, an excellent example, starting just above the [[aortic valve]] with reflection of [[aorta]] to show the dissection tract and some [[thrombus]]
:*10% arise in the transverse aortic arch
Image:Aortic aneurysm 11.jpg|Dissecting [[Aneurysm]]: Gross shows dilated [[aorta]] with extensive [[atherosclerosis]] dissection is seen, a small [[abdominal aorta]] [[atherosclerotic]] [[aneurysm]] is present good for association of [[dilation]] with dissection  
:*20% in the proximal descending aorta
Image:Aortic aneurysm 12.jpg|Dissecting [[Aneurysm]]: Gross arrow points to start of dissection in first portion [[aortic arch]] good but not the best example shows [[dilation]]
:*5% in the more distal descending aorta.
Image:Aortic aneurysm 13.jpg|Dissecting [[Aneurysm]]: Gross, very good to show start of dissection above [[aortic valve]] and blood in false channel.
Once a tear develops, blood then passes into the media, and a false leumen is dissected distally in the outer layer of aortic media involving ~50% of the aortic circumference. This false leumen can enlarge, and compress the true leumen, as well as extend proximally or distally and occlude aortic branches.  For some unknown reason, the right lateral wall of the ascending aorta is the most common site for dissection.
</gallery>
::* An aortic intramural hematoma can form when the vaso vasorum ruptures into the aortic wall.  This is distinguished from dissection by the lack of an intimal tear.  This disorder parallels aortic dissection in terms of prognosis when the ascending aorta or aortic arch is involved, and rapid surgical intervention is indicated.  Involvement of the descending aorta, however, carries a better prognosis than dissection, and outcome tends to be similar with medical or surgical therapy.
</div>


Aortic dissection is associated with [[hypertension]] (high blood pressure) and many [[connective tissue]] disorders.  [[Vasculitis]] ([[inflammation]] of an artery) is rarely associated with aortic dissection. It can also be the result of chest trauma. 72 to 80% of individuals who present with an aortic dissection have a previous history of hypertension.
<div align="left">
<gallery heights="175" widths="175">
Image:Aortic aneurysm 14.jpg|Dissecting [[Aneurysm]]: Gross, heart with root of [[aorta]] to show [[hemorrhage]] into [[pericardium]] (a very good example).
Image:Aortic aneurysm 15.jpg|Dissecting [[Aneurysm]]: Gross, of heart and [[aorta]] with dissection and large false channel (a good example).
Image:Aortic aneurysm 16.jpg|Dissecting [[Aneurysm]]: Gross cross section of [[aorta]] with two channels (a good example).
Image:Aortic aneurysm 19.jpg|Dissecting [[Aneurysm]]: Gross good example angular tear above [[aortic valve]].
</gallery>
</div>


The highest incidence of aortic dissection is in individuals who are 50 to 70 years old. The incidence is twice as high in males as in females (male-to-female ratio is 2:1). Half of dissections in females before age 40 occur during [[pregnancy]] (typically in the 3rd trimester or early [[postpartum]] period).
<div align="left">
<gallery heights="175" widths="175">
Image:Aortic aneurysm 18.jpg|Dissecting [[Aneurysm]]: Gross good example of typical angular tear above [[aortic valve]].
Image:Aortic aneurysm 25.jpg|Dissecting [[Aneurysm]]: Gross, rather well shown dissection in first portion of the [[aortic arch]]
Image:Aortic aneurysm 26.jpg|Dissecting [[Aneurysm]]: Gross, rather well shown dissection in first portion of the [[aortic arch]]
Image:Aortic aneurysm 27.jpg|Dissecting [[Aneurysm]]: Gross, an excellent example of type I [[lesion]]
</gallery>
</div>


[[Marfan syndrome]] is noted in 5-9% of individuals who suffer from aortic dissection. In this subset, there is an increased incidence in young individuals. Individuals with Marfan syndrome tend to have aneurysms of the aorta and are more prone to proximal dissections of the aorta.
<div align="left">
<gallery heights="175" widths="175">
Image:Aortic aneurysm 28.jpg|Dissecting [[Aneurysm]]: Gross, external view, an excellent example
Image:Aortic aneurysm 29.jpg|Dissecting [[Aneurysm]]: Gross, Type I shows false channel
Image:Aortic aneurysm 30.jpg|Dissecting [[Aneurysm]]: Gross, opened to show false channel (good example)
Image:Aortic aneurysm 36.jpg|Dissecting [[Aneurysm]]: Gross, large tear in first portion of [[aortic arch]], [[annuloaortic ectasia]]
</gallery>
</div>


[[Turner syndrome]] also increases the risk of aortic dissection, by aortic root dilatation<ref>[http://www.ncbi.nlm.nih.gov/sites/entrez?Db=PubMed&Cmd=ShowDetailView&TermToSearch=17055808&ordinalpos=2&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum Increased maternal cardiovascular mortality associated with pregnancy in women with Turner syndrome.]</ref>.
<div align="left">
<gallery heights="175" widths="175">
Image:Aortic aneurysm 32.jpg|Dissecting [[Aneurysm]]: Gross, coagulum of blood in false channel
Image:Aortic aneurysm 33.jpg|Dissecting [[Aneurysm]]: Gross, [[aortic valve]] area dissection (well shown, typical lesion)
Image:Aortic aneurysm 37.jpg|Dissecting [[Aneurysm]]: Gross, external view of heart and first portion of [[aortic arch]], [[annuloaortic ectasia]], [[hemorrhage]] beneath [[adventitia]] is evidence of dissection
Image:Aortic aneurysm 41.jpg|Dissecting [[Aneurysm]] in a patient with [[Marfan's syndrome]]
</gallery>
</div>


Chest trauma leading to aortic dissection can be divided into two groups based on etiology: blunt chest trauma (commonly seen in car accidents) and [[iatrogenic]]. Iatrogenic causes include trauma during [[cardiac catheterization]] or due to an [[intra-aortic balloon pump]].
<div align="left">
<gallery heights="175" widths="175">
Image:Aortic aneurysm 44.jpg|Dissecting [[Aneurysm]]: Gross, fixed tissue, [[descending aorta|descending]] [[thoracic aorta|thoracic]] segment dissection opened to show the false channel. The true surface is also visible
Image:Aortic aneurysm 48.jpg|Dissecting [[Aneurysm]]: Gross natural color [[descending aorta]] opened into false channel
Image:Aortic aneurysm 59.jpg|Dissecting [[Aneurysm]]: Gross natural color close-up view of [[aortic valve]] and [[proximal]] [[aortic arch]] with ruptured [[intima]] rather good illustration of this [[lesion]]
Image:Aortic aneurysm 62.jpg|Dissecting [[Aneurysm]] [[Chronic]]: Gross natural color first portion of [[aortic arch]] with [[intima]]l rent well shown with healed margins and view into false channel that shows a surface looking like [[atherosclerosis]] which is known to develop in a [[chronic]] dissection
Image:Aortic aneurysm 63.jpg|Dissecting [[Aneurysm]] [[Chronic]]: Gross, natural color, closer view of the previous one (a very good example)
</gallery>
</div>
==Microscopic Pathology==
{| align="left"
|[[File:Aortic dissection (2).jpg|thumb|none|200px|<ref>Case courtesy of Wikimedia Commons</ref>]]
|}


== References ==
== References ==
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[[CME Category::Cardiology]]


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Latest revision as of 18:07, 21 January 2020

Aortic dissection Microchapters

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Differentiating Aortic dissection from other Diseases

Epidemiology and Demographics

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Natural History, Complications and Prognosis

Diagnosis

Diagnostic Study of Choice

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Physical Examination

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Treatment

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Special Scenarios

Management during Pregnancy

Case Studies

Case #1


Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2] Sahar Memar Montazerin, M.D.[3]

Overview

Aortic dissection begins as a tear in the aortic wall in > 95% of patients. The tear is usually transverse, extends through the intima and halfway through the media and involves ~50% of the aortic circumference. Two thirds of dissections originate in the ascending aorta, and 20% are in the proximal descending aorta.

Pathophysiology

Normal Anatomy of the Aorta

As with all other arteries, the aorta is made up of three layers. The layer that is in direct contact with the flow of blood is the tunica intima, commonly called the intima. This layer is made up of mainly endothelial cells. Just deep to this layer is the tunica media, known as the media. This middle layer is made up of smooth muscle cells and elastic tissue. The outermost layer (furthest from the flow of blood) is known as the tunica adventitia or the adventitia. This layer is composed of connective tissue.
Blood penetrates the intima and enters the media layer.

Pathogenesis

Initial Intimal Tear

  • Aortic dissection begins as a tear in the aortic wall in > 95% of patients.
  • It is usually transverse, extends through the intima and halfway through the media and involves ~50% of the aortic circumference.

Location of Dissections

Propagation of the Intimal Tear

In an aortic dissection, blood penetrates the intima and enters the media layer. The high pressure rips the tissue of the media apart, allowing more blood to enter. This can propagate along the length of the aorta for a variable distance, dissecting either towards or away from the heart or both.

Once a tear develops, blood then passes into the media, and a false lumen is dissected in the outer layer of aortic media involving ~50% of the aortic circumference. This false lumen can enlarge, and compress the true lumen, as well as extend proximally or distally and occlude aortic branches. For some unknown reason, the right lateral wall of the ascending aorta is the most common site for dissection. The right coronary artery can become occluded as a result of this propagation.

Separating the false lumen from the true lumen is a layer of intimal tissue. This tissue is known as the intimal flap. As blood flows down the false lumen, it may cause secondary tears in the intima. Through these secondary tears, the blood can re-enter the true lumen.

Aortic Dissection in the Absence of an Intimal Tear

In about 13% of aortic dissections, there is no evidence of an intimal tear. It is believed that in these cases the inciting event is an intramural hematoma (caused by hemorrhage within the media). Since there is no direct connection between the true lumen and the false lumen in these cases, it is difficult to diagnose an aortic dissection by aortography if the etiology is an intramural hematoma. An aortic dissection secondary to an intramural hematoma should be treated the same as one caused by an intimal tear.

An aortic intramural hematoma can form when the vasa vasorum ruptures into the aortic wall. This is distinguished from dissection by the lack of an intimal tear. This disorder parallels aortic dissection in terms of prognosis when the ascending aorta or aortic arch is involved, and rapid surgical intervention is indicated. Involvement of the descending aorta, however, carries a better prognosis than dissection, and outcome tends to be similar with medical or surgical therapy.

Genetics

Genes involved in the pathogenesis of aortic dissection include:[1][2]

Associated Conditions

Conditions associated with aortic dissection include:[1]

Gross Pathology

Images shown below are courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology

  • Dissecting Aneurysm: Gross very good example dissected channel has been opened.

    Dissecting Aneurysm: Gross very good example dissected channel has been opened.

  • Dissecting Aneurysm: Gross external view good appearance from adventitia.

    Dissecting Aneurysm: Gross external view good appearance from adventitia.

  • Dissecting Aneurysm: Gross opened false channel.

    Dissecting Aneurysm: Gross opened false channel.

Microscopic Pathology

[3]

References

  1. ↑ 1.0 1.1 Pinard, Amélie; Jones, Gregory T.; Milewicz, Dianna M. (2019). "Genetics of Thoracic and Abdominal Aortic Diseases". Circulation Research. 124 (4): 588–606. doi:10.1161/CIRCRESAHA.118.312436. ISSN 0009-7330.
  2. ↑ Verhagen, Judith M.A.; Kempers, Marlies; Cozijnsen, Luc; Bouma, Berto J.; Duijnhouwer, Anthonie L.; Post, Jan G.; Hilhorst-Hofstee, Yvonne; Bekkers, Sebastiaan C.A.M.; Kerstjens-Frederikse, Wilhelmina S.; van Brakel, Thomas J.; Lambermon, Eric; Wessels, Marja W.; Loeys, Bart L.; Roos-Hesselink, Jolien W.; van de Laar, Ingrid M.B.H. (2018). "Expert consensus recommendations on the cardiogenetic care for patients with thoracic aortic disease and their first-degree relatives". International Journal of Cardiology. 258: 243–248. doi:10.1016/j.ijcard.2018.01.145. ISSN 0167-5273.
  3. ↑ Case courtesy of Wikimedia Commons

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