Corelations Of Gene Polymorphism Of Smooth Muscle Cell Contractile Dysfunction Path And Aortic Dissections

Aneurysms and dissections are the major diseases affecting the aorta and are a leading cause of morbidity and mortality in the United States. [5]The most common location for aortic aneurysms is in the infrarenal abdominal aorta, followed by the ascending thoracic aorta. Aortic dissections are classified according to the anatomic location of the initial tear in the aortic wall, with type A dissections initiating in the ascending thoracic aortic just above the aortic valve and type B dissections originating in the descending thoracic aortic just beyond the take-off of the subclavian artery. Without prophylactic surgical repair of the aorta, progressive enlargement of an ascending thoracic aortic aneurysm leads to a type A dissection; thus, thoracic aortic aneurysms and type A dissections (TAAD) are associated conditions.The aorta is composed of three layers:a thininner layer, the tunica intima; a thick middlelayer, the tunica media; and a thin outer layer, the tunica adventitia. The tensile strength and elasticity of the aorta reside in the medial layer, which is composed of concentrically arranged elastic fibers and smooth muscle cells (SMCs). The SMCs are longitudinally oriented and dispersed among the circular elastic fibers. By contracting in response to pulsatile blood flow, the SMCs regulate blood flow and pulse pressure. The pathological hallmark of TAAD is medial degeneration, which is characterized by loss and fragmentation of elastic fibers and accumulation of proteoglycans in the aorticmedia.Debate persists as to whether SMC loss or hyperplasia occurs in the aortic media associated with medial degeneration extends into the aortic wall [6]. Inflammatory cells often accompanymedial degeneration, but the role of inflammation in disease progression remains to be defined[7].Numerous genetic syndromes predisposeindividuals to TAAD. Most prominent among these syndromes is Marfan syndrome (MFS), where virtually every patient develops ascending aortic disease. Other genetic syndromesand disorders associated with TAAD include Loeys-Dietz syndrome, Ehlers-Danlos syndrome (vascular form), and filamin A mutations. However, most patients with TAAD do not have a genetic syndrome, although manyhave an inherited genetic predisposition for TAAD. This review focuses on the genes thatpredispose to TAAD and describes how the identification of these genes has provided in sights into the pathogenesis of this deadly disease.Chapter 1 A single nucleotide polymorphism in MYH11,MMP9,FBLN5 and TGFBR2 is associated with aortic dissectionObjective:To investigate the impact of the myosin heavy chain 11 gene((Rs1050113) polymorphisms on aortic dissection.Methods:Genomic DNA was isolated from blood from 105 patients with aortic dissection, and 105 control patients. The genotypings of 4 myosin heavy chain 11 single nucleotide polymorphisms (rs1050113,rs1050162,rs880071 and rs1050111) were determined by using single-base primer extension assays. Associations between polymorphisms and disease were estimated with odds ratios and their 95% confidence intervals.Results:The frequency of the rs1050111c>t was significantly lower in patients with aortic dissection (12.4%) compared to control (23.8%,P<0.05). Patients with aortic dissection were nearly 2 times less likely than control subjects to have the T allele (adjusted odds ratio,2.104; 95% confidence interval,1.012-4.374). There were no significant associations between the Rs1050113C> T,Rs1050162A> G, rs880071 G>A polymorphisms and thoracic aortic disease.Conclusions:The myosin heavy chain 11 rs1050111c>t polymorphism is associated with aortic dissection. Further studies are warranted to elucidate the functional role of the rs1050111c>t variant in myosin heavy chain 11 expression.Chapter 2 A single nucleotide polymorphism in MYH11,MMP9,FBLN5 and TGFBR2 is associated with PrognosisObjective:To investigate the impact of MYH11,MMP9. FBLN5 and TGFBR2 gene polymorphisms on Prognosis of aortic dissection.Methods:Genomic DNA was isolated from blood from 105 patients with aortic dissection, and 105 control patients. The genotypings of MYH11,MMP9,FBLN5 and TGFBR2 gene single nucleotide polymorphisms were determined by using single-base primer extension assays. Associations between polymorphisms and disease were estimated with odds ratios and their 95% confidence intervals.Results:The frequency of the myosin heavy chain 11 rs1050162G>A AA genotyping was significantly higher in aortic dissection patients with SAE compared to GA and GG genotyping (P<0.05). Aortic dissection patients with SAE were nearly 2 times less likely than G allele to have the A allele (adjusted odds ratio, 2.033,95% confidence interval,0.717,5.764).Conclusions:The myosin heavy chain 11 rs1050162G>A polymorphism is associated with aortic dissection with MACE. Further studies are warranted to elucidate the functional role of the rs1050162G>A variant in myosin heavy chain 11 expression.