Serial ai based comprehensive coronary physiological assessment before and after intensive lipid lowering therapy: YELLOW III substudy

Background While intensive lipid-lowering favourably modifies coronary plaque morphology, its effects on angiography-derived coronary physiology and arterial mechanics remain unclear. Radial wall strain (RWS), Murray law based quantitative flow ratio (μFR), and angiography-derived microvascular resistance (AMR) enable comprehensive wire-free assessment of plaque vulnerability and coronary physiology Purpose We evaluated the impact of intensive lipid-lowering therapy on serial 6-month changes in RWS, μFR, AMR and whether these effects differ between focal and diffuse coronary artery disease (CAD) Methods YELLOW III was a prospective, paired imaging study of patients with stable CAD and lipid-rich, non-obstructive plaques treated with Evolocumab added to high-intensity statin therapy. Coronary angiography and intravascular imaging was performed at baseline and 26 weeks. μFR, RWS, AMR, and virtual pullback pressure gradient (PPG) were analyzed by a blinded core laboratory Results 220 coronary vessels (110 paired baseline and follow-up) were analyzed. Evolocumab therapy was associated with modest but significant improvement in epicardial physiology (both vessel-level µFR and lesion-level ΔµFR improved following maximal lipid lowering therapy [µFRvessel: 0.88 ± 0.084 vs. 0.89 ± 0.088, p < 0.001; ΔµFRlesion: 0.069 ± 0.063 vs. 0.077 ± 0.081, p = 0.028]). and reduction in RWS (16.9 ± 4.2% vs. 14.9 ± 3.5%; p<0.001). AMR did not change (23.2 ± 5.3 vs. 23.8 ± 4.9 mmHg·s/dm; p=0.28). Virtual PPG improved modestly (PPGi: 0.61 ± 0.084 vs. 0.63 ± 0.092, p = 0.038), without systematic reclassification of focal versus diffuse disease. 30% of vessels were reclassified over time; however, overall disease pattern distribution remained unchanged, with a numerically greater transition from diffuse to focal than focal to diffuse disease (17/90, 18.9% vs. 10/90, 11.1%; p = 0.248). While MaxLCBI₄mm was comparable between focal and diffuse disease, diffuse CAD was associated with a higher frequency of LCBI response (82.2% vs. 71.1%, p<0.001). Conclusions Intensive lipid lowering with Evolocumab improves epicardial coronary physiology and reduces RWS without affecting microvascular resistance. Diffuse CAD demonstrates greater lipid responsiveness, suggesting a biologically distinct and therapeutically modifiable disease phenotype.