Abstract Body (Do not enter title and authors here): Introduction
Calcific aortic valve disease (CAVD) is the most common valvular disorder with aortic valve calcification (AVC) as a principal underlying mechanism. Low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) [Lp(a)] are risk factors for AVC and aortic stenosis (AS). However, whether an interaction between LDL-C and Lp(a) exists in CAVD is not well studied, which may have implications for trials investigating novel Lp(a) lowering therapies.

Methods
Cardiac computed tomography (CT) was used to quantify AVC in participants free of known cardiovascular disease at Multi-Ethnic Study of Atherosclerosis (MESA) Visit 1 and subsequent visits. Incident severe AS was adjudicated through chart review of hospital visits and echocardiogram data. Participants were categorized into four groups based on the cutpoints of LDL-C 160mg/dL and Lp(a) 50mg/dL. We examined the association of the four LDL-C and Lp(a) groups with incident AVC and incident severe AS using multivariable adjusted Cox Hazard models. We also tested for the presence of a multiplicative interaction between LDL-C and Lp(a).

Results
In this analysis, 6,603 participants were included. The mean age of participants was 62 years old and 52% were women. Incident AVC occurred among 416 participants and during a median follow-up time of 17 years, 84 participants developed severe AS. At baseline, AVC >0 was present in 11.9% of participants with LDL-C <160mg/dL and Lp(a) <50mg/dL compared to 21.6% participants with LDL-C ≥160mg/dL and Lp(a) ≥50mg/dL (p=<0.01). Compared to participants with LDL-C <160 mg/dL and Lp(a) <50mg/dL, those with LDL-C ≥160 and Lp(a) ≥50 mg/dL had a 2.3-fold higher risk for incident AVC [HR 2.27 (1.34-2.85)] (Table 1). There was a statistically significant multiplicative interaction between Lp(a) and LDL-C as continuous variables for both incident AVC (p=0.002) and severe AS (p=0.036).

Conclusion
Participants with both an elevated LDL-C and Lp(a) had the highest risk for incident AVC. There was a significant interaction between LDL-C and Lp(a) for both incident AVC and incident AS. Thus, individuals with elevated LDL-C and Lp(a) may be most likely to benefit from novel Lp(a) lowering therapies and/or combined LDL-C and Lp(a) lowering.