CO47 | Genetic characterization of the <i>KIV2 LPA</i> polymorphism in subjects with bicuspid aortic valve with different clinical complications

Background and Aims: The bicuspid aortic valve (BAV) is the most common congenital cardiopathy affecting 0.5 to 2.0% of the general population. This condition can cause secondary complications such as valvular aortic stenosis, calcification, aortic insufficiency and thoracic aortic aneurysm. Beyond hemodynamic valvular impairment, a frequent determinant of BAV natural history, dyslipidemia and elevated lipoprotein (a) [Lp(a)] levels also favour progression and complications of BAV disease. Lp(a) levels are known to be under a strict genetic control (heritability of the trait >90%) and are largely influenced by LPA Kringle IV type 2 (KIV2) size polymorphism: a lower number of KIV2 repeats is associated with higher levels of circulating Lp(a). In this study, we characterized LPA KIV2 repeats, using a digital droplet PCR (ddPCR) approach, in a cohort of BAV patients with different clinical settings. Methods: One hundred nine subjects of Caucasian origin referred to the Regional Referral Center for Marfan syndrome and related disorders and to the Advanced Molecular Genetics Laboratory (Atherothrombotic Diseases Center, AOU-Careggi) were enrolled. Patients were divided into two groups according to different clinical settings: 1) patients undergoing valve replacement surgery (VRS, n=68 subjects) and 2) patients not undergoing valve replacement surgery (NVRS, n=41 subjects). The genetic characterization of the LPA KIV2 polymorphism was carried out through ddPCR (Bio-Rad). Results: NVRS and VRS patients showed, respectively, significant differences in median age (IQR) [45 (28-52) vs. 66 (57–75), p<0.001], and in classical cardiovascular risk factors such as dyslipidaemia [11 (16.2%) vs. 19 (46.3%), p=0.0009], hypertension [20 (29.4%) vs. 26 (63.4%), p=0.0007], and smoking habit [7 (10.3%) vs. 23 (56.1%), p=0.0001], as expected. The prevalences of aortic stenosis, calcification and aortic root/thoracic ascending aorta dilatation, according to different severity degree in both groups, are reported in the enclosed Table 1.We also observed a significant difference in the median number of KIV2 repeats between the two groups [13 (8.1 – 22.6) in NVRS vs. 33.6 (19.1 – 42.9) in VRS, p<0.001]. As concerns KIV2 repeat evaluation according to BAV clinical complications, NVRS patients with complications showed a trend towards reduction in the number of KIV2 repeats with respect to NVRS patients without complications [stenosis: 10,90 (7.1 – 19.9) vs. 13.21 (9.2 – 24.4), p=0.341; calcification: 12.6 (7.2 – 20.3) vs. 15 (9.88 – 24.5), p=0.319; root dilatation: 11.9 (6.9 – 18.6) vs. 15.8 (10.4 – 24.0), p=0.165]. Moreover, we observed a statistically significant decrease in KIV2 repeats number in NVRS patients with thoracic ascending aorta dilatation with respect to those without dilatation [11.2 (6.7 – 17.6) vs. 18.8 (11.8 – 25.9), p=0.016]. In VRS patients, instead, no significant difference in the distribution of the number of KIV2 repeats, according to the presence or absence of BAV clinical complications, was found. Conclusions: Our analysis suggests that in NVRS patients, younger and with a lower prevalence of traditional cardiovascular risk factors than VRS ones, higher levels of genetically determined lipoprotein (a) might contribute to the development of BAV complications and in turn to a worse prognosis. Data observed in VRS patients might be likely due to the not negligible impact of cardiovascular risk factors burden in influencing the phenotype severity.