Clinical and Genetic insights in a tertiary care center cohort of patients with bicuspid aortic valve

BACKGROUND to describe spectrum of valve function in bicuspid aortic valve (BAV) patients referred to a tertiary care center and to investigate genetic pathways associated with valve degeneration. METHODS All consecutive patients with BAV were prospectively included from 2014 to 2018. BAV was defined according to embryologic and Sievers classifications. Clinical and echo variables were compared according to aortic valve function. Aortic valve tissues were collected from BAV patients (n=15) operated for severe aortic stenosis (AS-BAV, n=7) or aortic regurgitation (AR-BAV, n=8). RT-qPCR was performed to compare gene expression level in AS-BAV, AR-BAV and controls corresponding to healthy tricuspid aortic valves collected on human heart explant immediately after transplantation (n=5). RESULTS Out of 223 adults with BAV, mean age 53±17 years, 83% had left-right coronary cusps fusion, 80% Sievers type 1 BAV and 49% aortopathy. Twenty-four patients had normal valve function, 66 patients had AS-BAV, 91 patients had AR-BAV and 40 patient had AR+AS BAV. BAV phenotype did not predict neither AS-BAV nor AR-BAV (all p>0.1). By multivariable analysis, age >50 (41.6[10.3-248.2],p<0.001) and presence of raphe(12.8[2.4-87.4],p<0.001) were significantly associated with AS-BAV and male gender of AR-BAV(5[1.6-16.4], p=0.005). RT-qPCR revealed overexpression of RUNX2 in AS-BAV (17.67±1.83 vs 3.25±0.93, p=0.04), and overexpression of COL1A1 (4.01±0.6vs2.25±0.5,p=0.03) and FLNA (23.31±7.5vs1.97±0.3,p=0.03) in AR-BAV. CONCLUSIONS This prospective study confirmed high prevalence of valve dysfunction at first diagnosis of BAV in a referred population. Clinical and echo variables are poorly associated with BAV dysfunction. The leaking or stenotic processes could be both supported by dysregulation of specific genetic pathways