Abstract 244: Differential mRNA Expressions in Thoracic Aortic Aneurysm in Patients with Bicuspid and Tricuspid Aortic Valve

Abstract

Objective: Bicuspid aortic valve (BAV), the most common congenital heart condition, is frequently associated with thoracic aortic aneurysm (TAA). Aortic mRNA expression patterns in BAV patients and expression differences between BAV and tricuspid aortic valve (TAV) patients are unclear. We sought to compare mRNA expressions in TAA in patients with BAV and TAV. Methods and Results: Ascending aorta tissue was obtained from 58 aortic aneurysm repair patients (31 BAV, 27 TAV) and from 8 heart transplant donors. Illumina Human HT-12v4 microarrays were used to assess mRNA expression. After standard QC and filtering, probes were analyzed using multivariable linear regression analysis, adjusting for age, gender, medication use (beta blockers, ACE-Is, ARBs), and 10 surrogate variables. Ingenuity Pathway Analysis (IPA) was used to identify pathways and top regulator effect networks that were differentially expressed in BAV vs. TAV and BAV vs. donors. In BAV vs. TAV, MMP9, ESM1 and IL1B were downregulated 0.63, 0.74 and 0.77 fold, whereas COMP was upregulated 2.29 fold (p < 0.05 for all). In BAV vs. donors, IL1R2, MCEMP1, IL18RAP and ACAN were downregulated 0.66, 0.2, 0.2 and 0.05 fold, while ADAMTS8, CCL21 and CIDEA were upregulated 6.97, 6.24 and 4.65 fold (p < 0.0001). IPA analysis showed P53 as the top upstream regulator for both BAV vs. TAV (p = 1.9e-8) and BAV vs. donors (p = 2.3e-25). IRF7, which protects against angiotensin II-induced hypertrophy in cardiomyocytes, was also a significant upstream regulator for BAV vs. TAV (p = 3.6e-7). Additionally, miR-124-3p in BAV vs. TAV (p = 6.3e-7) and BAV vs. donors (p = 1.7e-22), as well as miR-96-5p in BAV vs. TAV (p = 4e-7) were predicted significant upstream regulators. Immune response was shown to be the top regulator effect network in BAV vs. TAV, whereas perivascular fibrosis was shown to be an important regulator effect network in BAV vs. donors. Cell stress pathways were also activated in BAV vs. donors. Conclusions: Distinct pathways and regulator effect networks exist in TAA with BAV or TAV. TAV associated TAA is more associated with inflammatory responses, while BAV aortopathy is more associated with extracellular matrix remodelling and cell stress. MiRs may also play an important role in BAV aortopathy.