Lipoprotein(a) and hs-CRP interplay as a driver of polyvascular atherosclerosis and cardiovascular events

Background and Aim Lipoprotein(a) [Lp(a)] is a genetically determined risk factor for cardiovascular disease, yet its pro-atherogenic potency in the absence of acute inflammation remains debated. We aimed to investigate whether the impact of Lp(a) on subclinical atherosclerosis and adverse clinical outcomes is dependent on systemic inflammation (hs-CRP). Methods We analyzed participants from the Athens Angiometabolic Cohort (AAC), n=784, excluding patients with acute coronary syndromes. The final population consisted of individuals with no known coronary artery disease (non-CAD) and patients with stable CAD. Subclinical atherosclerosis was quantified using carotid and femoral ultrasonography (Sum of Wall Thickness - SumWT) and arterial stiffness via Pulse Wave Velocity (PWV). Participants were stratified into four phenotypes based on Lp(a) (cut-off 125nmol/) and hs-CRP (cut-off 2.0 mg/L). Findings were prospectively validated in the ATTICA study (n=2,126) over a 20-year follow-up for MACE and 10-year CV death using Cox proportional hazard models adjusted for SCORE2. Results In the AAC study, elevated Lp(a) alone (Group 3: High Lp(a)/Low hs-CRP) was not significantly associated with increased carotid SumWT (OR: 2.85, p=0.15) or femoral SumWT (OR: 0.79, p=0.85) (Table 1). Conversely, elevated hs-CRP alone (Group 2: Low Lp(a)/High hs-CRP) was associated with both carotid (OR: 2.77, p=0.024) and femoral (OR: 2.94, p=0.027) atherosclerosis. However, a potent synergistic effect was observed in the "Double Hit" phenotype (Group 4: High Lp(a)/High hs-CRP), which conferred the highest risk for carotid SumWT (OR: 4.1, p=0.041) and femoral SumWT (OR: 3.6, p=0.037) (Table 1). Most notably, the coexistence of high Lp(a) and high hs-CRP was the only significant predictor of polyvascular disease (simultaneous involvement of ≥2 vascular beds), demonstrating a six-fold increase in risk (OR: 6.26, 95% CI: 1.91–20.5, p=0.002) (Table 1). No significant associations were found with PWV >10 m/s. In the prospective ATTICA validation, Group 4 exhibited a significant and sustained risk for CV death at 10 years (HR: 2.17, p=0.009) and MACE at 20 years (HR: 1.90, p=0.004) (Table 2). Notably, Group 3 (High Lp(a)/Low hs-CRP) showed no increased risk at any time point (p>0.05). Kaplan-Meier curves confirmed early divergence for Group 4 for 20 year MACE (Figure 1). Conclusions Our findings suggest that systemic inflammation acts as a significant modifier of Lp(a)-associated cardiovascular risk. While elevated Lp(a) is a known risk factor, its pathogenicity is markedly amplified in a pro-inflammatory environment, leading to accelerated polyvascular atherosclerosis and increased long-term mortality. These data support a more integrated approach to risk stratification, suggesting that patients with the "Double Hit" phenotype may represent a priority group for aggressive preventive interventions targeting both lipid and inflammatory pathways.