Aortic aneurysm pathophysiology
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Overview
It is thought that aortic aneurysm is the result of either genetic disturbances and environmental risks such as smoking.
Pathophysiology
The aortic aneurysms are a multifactorial disease associated with genetic and environmental risk factors. Marfan's syndrome and Ehlers-Danlos syndrome are associated with the disease, but there are also rarer syndromes like the Loeys-Dietz syndrome that are associated as well. Even in patients that do not have genetic syndromes, it has been observed that genetics can also play a role on aortic aneurysms' development. There has been evidence of genetic heterogeneity as there has already been documented in intracranial aneurysms.[1] The genetic alterations associated with these genetic syndromes are the following:
| Disease | Involved Cellular Pathway | Mutated Gene(s) | Affected Protein(s) |
|---|---|---|---|
| Ehlers-Danlos syndrome type IV | Extracellular Matrix Proteins | COL3A1 | Collagen type III |
| Marfan's syndrome | Extracellular Matrix Proteins | FBN1 | Fibrillin-1 |
| Loeys-Dietz syndrome | TGF-β Pathway | TGFBR1/TGFBR2 | |
| Aneurysm-Osteoarthritis Syndrome | SMAD3 | SMAD3 | |
| Autosomal Dominant Polycystic Kidney Disease | Ciliopathy | PKD1PKD2 | Polycystin 1
Polycystin 2 |
| Turner Syndrome | Meiotic Error with Monosomy, Mosaicism, or De Novo Germ Cell Mutation | 45X
45XO |
Partial or Complete Absence of X Chromosome |
| Bicuspid Aortic Valve with TAA | Neural Crest Migration | NOTCH1 | Notch 1 |
| Familial TAA | Smooth Muscle Contraction Proteins | ACTA2 | α-Smooth Muscle Actin |
| Familial TAA with Patent Ductus Arteriosus | Smooth Muscle Contraction Proteins | MYH11 | Smooth Muscle Myosin |
| Familial TAA | Smooth Muscle Contraction Proteins | MYLK | Myosin Light Chain Kinase |
| Familial TAA | Smooth Muscle Contraction Proteins | PRKG1 | Protein Kinase c-GMP Dependent, type I |
| Loeys-Dietz Syndrome variants | TGF-β Pathway | TGF-βR1TGF-βR2SMAD3TGF-β2TGF-β3 |
These genetic diseases mostly affect either the synthesis of extracellular matrix protein or damage the smooth muscle cells both important component's of the aortic wall. Injury to any of these components lead to weakening of the aortic wall and dilation - resulting in aneurysm formation.
The aorta is the largest vessel of the body, but it is not homogenous. Its upper segment is composed by a larger proportion of elastin in comparison to collagen, therefore being more distensible. The lower segment has a larger proportion of collagen, therefore it is less distensible. It is also where most of the atherosclerotic plaques of the aorta are located.[3] Historically it was thought that abdominal and thoracic aortic aneurysms were caused by the same etiology: atherosclerotic degeneration of the aortic wall, but recently it has been theorized that they are indeed different diseases.[3]
The aortic arch mostly derives from the neural crest cell which differentiate into smooth muscle cells. These smooth muscle cells are probably more adapted to remodel the thoracic aorta and manage the higher pulse pressure and ejection volume due to increased production of elastic lamellae during development and growth.[3] The abdominal aorta remains with cells of mesodermal origin, which are more similar to that of the original primitive arterial. That difference results in the neural crest cell precursors of the thoracic aorta being able to respond differently to various cytokines and growth factors than the mesodermal precursors of the abdominal aorta,[4] such as homocysteine[5] and angiotensin II.[6]
When neural crest vascular smooth muscle cells are treated with TGF-β they demonstrate increased collagen production, while mesodermal vascular smooth muscle cell did not.[7] Not coincidently, mutations of the TGF-β receptor can cause thoracic aortic aneurysm but do not cause abdominal aortic ones.
The thoracic and abdominal aorta are very structurally different. While they both have three layers: intimal, medial and adventitia, the media of the thoracic aorta is comprised of approximately 60 units divided into vascular and avascular regions. The abdominal aorta consists of about 30 units and is entirely avascular - being dependent on trans-intimal diffusion of nutrients for its smooth muscle cells to survive.[8] It is believed that both differences explain why the abdominal aorta is more likely to form aneurysms.
The development of aortic aneurysms is defined by: inflammation: infiltration of the vessel wall by lymphocytes and macrophage; extracellular matrix damage: destruction of elastin and collagen by proteases (also metalloproteinases) in the media and adventitia; cellular damage: loss of smooth muscle cells with thinning of the media; and insufficient repair: neovascularization.[9]
In summary:
- The pathogenesis of aortic aneurysm is characterized by progressive dilation, rupture, and may present with dissection;
- The pathological processes that lead to abdominal and thoracic aortic aneurysms may be very different from one another;
- The fibrillin-1 gene mutation has been associated with the development of thoracic aortic aneurysms in Marfan's syndrome;
- Other gene mutations coding for collagen, elastin and other elements of the extracellular matrix have been associated with the development of aneurysms in some genetic disorders, including Ehlers-Danlos syndrome and others;
- Mutations in the TGF-β pathway have also been described in the pathogenesis of aortic aneurysms in multiple genetic disorders, including Loeys-Dietz syndrome.
References
- ↑
- ↑ Bhandari, R., Kanthi, Y. - The Genetics of Aortic Aneurysms - The American College of Cardiology - available at:https://www.acc.org/latest-in-cardiology/articles/2018/05/02/12/52/the-genetics-of-aortic-aneurysms
- ↑ 3.0 3.1 3.2
- ↑ Ruddy JM, Jones JA, Ikonomidis JS. Pathophysiology of thoracic aortic aneurysm (TAA): is it not one uniform aorta? Role of embryologic origin. Progress in cardiovascular diseases. 2013;56(1):68–73.
- ↑ Steed MM, Tyagi SC. Mechanisms of cardiovascular remodeling in hyperhomocysteinemia. Antioxidants & redox signaling. 2011;15(7):1927–1943.
- ↑ Bruemmer D, Daugherty A, Lu H, Rateri DL. Relevance of angiotensin II-induced aortic pathologies in mice to human aortic aneurysms. Ann N Y Acad Sci. 2011;1245:7–10.
- ↑ Gadson PF, Jr, Dalton ML, Patterson E, et al. Differential response of mesoderm- and neural crest-derived smooth muscle to TGF-beta1: regulation of c-myb and alpha1 (I) procollagen genes. Experimental cell research. 1997;230(2):169–180.
- ↑ Wolinsky H, Glagov S. Comparison of abdominal and thoracic aortic medial structure in mammals. Deviation of man from the usual pattern. Circulation research. 1969;25(6):677–686.
- ↑ Ailawadi G, Eliason JL, Upchurch GR Jr. Current concepts in the pathogenesis of abdominal aortic aneurysm. J Vasc Surg 2003;38:584-8.