Aortic aneurysm and dissection are associated with significant morbidity and mortality, accounting for more than 10,000 and contributing to more than 17,000 deaths annually in the United States1. Numerous risk factors for aneurysms have been identified, although they differ depending on the segment of the aorta involved. Aneurysmal disease in humans has been shown to involve the strong influence of hereditary predisposition and genetic discovery has been progressing at an intensifying pace.

Genetic determinants are now understood to represent a major factor in determining aneurysmal risk for the individual patient and genetic testing is regular feature of clinical practice. In addition to clinical utility, genetic discovery has identified novel aspects of vascular biology that reveal cellular and tissue events contributing to aortic aneurysm, which may, in turn, offer new therapeutic targets.


Marfan syndrome

The study of genetically triggered aortic disease has often been focused on Marfan syndrome, but the work has advanced the understanding and of TAA more broadly. Key accomplishments of MFS research include establishing the link between progressive aortic growth and aortic dissection (AoD)40, 41, demonstrating the benefits of prophylactic aortic root surgery to prevent AoD42, and, most recently, introducing medical therapies directed at pathologic signaling events within the aortic wall. However, one must be careful not to be complacent in concluding that aortic dissection arises purely from progressive aneurysmal growth of the aorta. Indeed, sporadic type A and type B AoDs often occur at aortic dimensions not usually considered aneurysmal.

Loeys-Dietz and Shprintzen-Goldberg syndrome

The association of TGF-β signaling with aortic aneurysm was affirmed through the surprising description of mutations in the genes TGFBR1 and TGFBR2  causing a human thoracic aortic aneurysm condition. LDS demonstrates many overlapping phenotypes with MFS, including chest wall deformity, pes planus, highly arched palate, and, most significantly, aortic root aneurysms.

Bicuspid Aortic Valve/ Thoracic Aortic Aneurysm

Bicuspid aortic valve (BAV) is the most common developmental malformation of the heart, affecting between 0.5–1% of the general population. In about 40–50% of those with BAV there is an associated dilatation of the ascending thoracic aorta (or aortic root). Therefore BAV-associated TAA (BAV/TAA) is likely the most common type of aneurysm affecting humans. Familial predisposition in BAV/TAA is a well-established; indeed, it is so common that screening of first-degree relatives is recommended in routine clinical practice. Some forms of monogenic TAA have a high predisposition for BAV such as LDS, ELN-related cutis laxa, and TAA associated with LOX mutations amongst others, however these conditions likely only represent a very small fraction of human BAV disease.

Pathogenic Models of Genetically-Triggered Aortic Disease

Research in experimental aneurysm has repetitively revealed overactivity of the TGF-β pathway in TAA43. Furthermore, the additional evidence of human mutations in genes encoding effectors of canonical TGF-β signaling have lead to the hypothesis that aberrant TGF-β signaling drives aneurysm progression43. Although postnatal observations of increased TGF-β signaling are robust, genetic perturbations tend to result in loss of TGF-β signaling potency, illustrating the complexity of the signaling perturbation.

Extracellular Matrix Genes and the Relationship to Matrix-Independent Gene Groups

Conduit arteries such as the aorta have one primary function: to accept the output of ventricular systole and carry blood to target organs. The engineering requirements of this function primarily involve components of the ECM; collagens (primarily I and III), elastin, and microfibrils necessary to provide structure and strength. Pathologic observations of aortic tissue have consistently noted striking abnormalities of the ECM of the aortic media with elastin fiber fragmentation and VSMC disarray. It therefore comes as no surprise that defects in members of the ECM itself cause aneurysm when dysfunctional. In humans, examples include genetic variation in genes encoding ECM proteins, such as fibrillins (FBN1), collagens (COL3A1), elastin (ELN), and matrix-stabilizing enzymes such as fibulin-4 (EFEMP2) and lysyl oxidase (LOX) a copper-containing oxidase responsible for cross linking of collagens and elastin.


Implications for Therapy

Just as we’ve come, over the years, to recognize that the thoracic aorta behaves differently from the abdominal aorta and, further still, that the ascending thoracic aorta behaves differently from the descending thoracic aorta, so too have we come to appreciate that TAAs of different etiologies can behave quite differently. Indeed, because BAV-associated TAAs are genetically mediated and demonstrate medial degeneration histologically, for many years experts had thought that such aneurysms were especially vulnerable to AoD, just as in MFS. However, a recent study found that in patients presenting with an acute AoD, the mean aortic diameter among those with an underlying BAV was actually significantly larger (i.e., not smaller) than among those with tricuspid aortic valves, refuting that the notion that a genetic underpinning predicts more virulent disease. Conversely, many patients with MFS suffer type B AoD at aortic diameters that are quite normal.



Disease Condition ,Peripheral vascular diseases,Thoracic Aortic Aneurysm