**Background:** Lipoprotein(a) [Lp(a)] is a causal risk factor for calcific aortic valve stenosis (CAVS). C-reactive protein (CRP), a biomarker of systemic inflammation, has been shown to interact with Lp(a) in predicting coronary artery disease risk, but whether such an interaction exists for CAVS was unknown. This study aimed to determine whether CRP levels modify the association between Lp(a) and CAVS incidence and progression.
**Methods:** The authors analyzed three independent cohorts. EPIC-Norfolk included 18,226 participants (406 incident CAVS cases) aged 45–79 years from the UK, followed for a median of 16 years. UK Biobank included 438,260 participants (4582 incident CAVS cases) aged 40–69 years, followed for a median of 12.5 years. The ASTRONOMER trial included 220 patients with pre-existing mild-to-moderate CAVS (peak aortic jet velocity 2.5–4.0 m/s) followed for a median of 3.5 years. Lp(a) was measured using immunoturbidimetric assays in all cohorts. CRP was measured and participants were stratified as <2 mg/L vs ≥2 mg/L. In EPIC-Norfolk, Lp(a) threshold was 50 mg/dL; in UK Biobank, 125 nmol/L; in ASTRONOMER, patients were stratified by tertiles (3rd tertile ≥58.5 mg/dL). Multivariable Cox proportional hazard models adjusted for age, sex, BMI, blood pressure, LDL cholesterol, creatinine, and smoking were used for incidence analyses. Two-way ANOVA was used for progression analyses.
**Key Results:** In EPIC-Norfolk, compared to participants with low Lp(a) (<50 mg/dL) and low CRP (<2 mg/L), those with high Lp(a) and low CRP had HR=1.86 (95% CI, 1.30–2.67) and those with high Lp(a) and high CRP had HR=2.08 (95% CI, 1.44–2.99). Participants with low Lp(a) and high CRP were not at higher risk (HR=1.09, 95% CI, 0.86–1.39). In UK Biobank, compared to low Lp(a) and low CRP, those with high Lp(a) and high CRP had HR=1.88 (95% CI, 1.69–2.08) and those with high Lp(a) and low CRP had HR=1.65 (95% CI, 1.51–1.82). Low Lp(a) with high CRP showed a modest increased risk (HR=1.19, 95% CI, 1.11–1.28). CAVS event rates in EPIC-Norfolk were 1.71% (low Lp(a)/low CRP), 2.57% (low Lp(a)/high CRP), 3.35% (high Lp(a)/low CRP), and 4.9% (high Lp(a)/high CRP). In UK Biobank, rates were 0.79%, 1.26%, 1.32%, and 1.89%, respectively. In ASTRONOMER, patients in the top Lp(a) tertile with high CRP had significantly faster Vpeak progression (0.29 ± 0.12 m/s/yr) vs those in the bottom two Lp(a) tertiles with low CRP (0.15 ± 0.06 m/s/yr, P=0.03). However, CAVS progression was comparable in patients with elevated Lp(a) with or without elevated CRP.
**Clinical Implications:** This study demonstrates that Lp(a) predicts CAVS incidence regardless of CRP levels, suggesting that systemic inflammation does not significantly modify Lp(a)-associated CAVS risk. These findings support the investigation of Lp(a)-lowering therapies for CAVS prevention and treatment independent of inflammatory status. The modestly higher risk in patients with both elevated Lp(a) and CRP may reflect higher absolute CAVS risk rather than a biological interaction. Limitations include the post-hoc nature of the ASTRONOMER analysis, lack of echocardiographic confirmation in population-based cohorts, predominantly European ancestry, and inability to distinguish bicuspid vs tricuspid valve phenotypes.