Impact of elevated lipoprotein(a) on epicardial coronary flow conductance and endoluminal atherosclerotic disease distribution

Background: Elevated lipoprotein(a) [Lp(a)] is associated with accelerated progression of coronary plaques, a higher prevalence of thin-cap fibroatheroma, and an increased risk of spontaneous myocardial infarction. However, Lp(a)'s impact on coronary artery disease (CAD) and the resulting coronary flow dynamics have yet to be fully determined. Objective: To evaluate the effects of elevated Lp(a) levels on epicardial coronary flow and endoluminal disease pattern (focal or diffuse). Methods: In a propensity-score matched (PSM) cohort from the ongoing PIONEER IV trial (NCT04923191), participants with de novo CAD and elevated Lp(a) (>50 mg/dL or 120 nmol/L) were matched to controls based on traditional CAD risk factors. Epicardial flow velocity was assessed using the Quantitative Flow Ratio (QFR), with the virtual QFR-Pressure Pullback Gradient Index (QFR-PPGi) characterizing the endoluminal disease phenotype. A QFR ≤ 0.80 indicated significant epicardial flow limitation. Results: Among 672 consecutively enrolled participants with available Lp(a) measurements, elevated levels were observed in 23 % (152/672). Complete risk profiles for traditional CAD risk factors were available for 391 participants with de novo CAD, of whom 75 had elevated Lp(a) levels. After propensity matching, 75 pairs (150 participants) were eligible for analyses. QFR analyses were completed in 392/450 (87 %) vessels. The median difference in baseline QFR between matched vessels was −0.045 (p = 0.005), while the mean difference in QFR-PPGi was −0.028 (p = 0.013). Vessels from participants with elevated Lp(a) demonstrated significantly higher rates of QFR ≤ 0.80 compared to matched controls (31 % vs. 19 %, absolute risk difference 12 %; 95 % CI: 2.7 %–21 %, p = 0.011). Conclusions: Elevated plasma levels of Lp(a) were associated with increased epicardial flow limitation and a more diffuse endoluminal disease pattern. Condensed abstract: In this PIONEER IV sub-study (NCT04923191), we investigated the effect of elevated lipoprotein(a) [Lp(a)] on epicardial coronary flow and endoluminal disease distribution. We analyzed 392 vessels from 75 propensity-matched pairs using Quantitative Flow Ratio (QFR) to assess flow limitation and the virtual QFR-Pressure Pullback Gradient Index (QFR-PPGi) to characterize disease distribution patterns (focal versus diffuse). Vessels exposed to elevated Lp(a) exhibited significantly higher rates of epicardial flow limitation (QFR ≤ 0.80) than controls (31 % vs. 19 %, absolute risk difference 12 %; 95 % CI: 2.7 %–21 %, p = 0.011). The median difference in baseline QFR between matched vessels was −0.045 (p = 0.005), while the mean difference in QFR-PPGi was −0.028 (p = 0.013). These findings demonstrate that elevated Lp(a) levels are associated with both greater epicardial flow limitation and a more diffuse pattern of coronary artery disease.