Unlocking the inflammatory 'code' in multivessel coronary disease: pathological network mediated by the PCSK9-NLRP3 axis and a novel microcirculatory dysfunction prediction model

Background Multivessel coronary disease (MVD) increases major adverse cardiovascular event (MACE) risks, but early diagnosis and prediction of post-PCI coronary microvascular dysfunction (CMD) remain challenging. Proprotein convertase subtilisin/kexin type 9 (PCSK9) and NLRP3 inflammasome are implicated in atherosclerosis, yet their roles in MVD pathogenesis and therapeutic potential require clarification. Objective This study investigated PCSK9 expression in MVD patients, its correlation with NLRP3 inflammasome and downstream factors (TLR4, IL-1β, IL-18), and its predictive value for MVD and post-PCI CMD. Additionally, we assessed probucol’s effects on inflammatory markers and PCSK9 levels. Methods 247 suspected CAD patients underwent coronary angiography (CAG), categorized into non-CAD (n=73), single-vessel disease (SVD, n=67), and MVD (n=107) groups. Serum PCSK9, NLRP3, TLR4, IL-1β, and IL-18 levels were measured via ELISA. MVD severity was quantified using Gensini/SYNTAX scores; CMD was diagnosed via angiography-derived microcirculatory resistance (AMR) index. ROC analysis evaluated PCSK9’s predictive performance. In MVD patients, 36 received atorvastatin+probucol (intervention) and 43 received atorvastatin alone (control). Inflammatory markers were reassessed post-treatment. Results 1. MVD patients had higher diabetes prevalence (42.1% vs. 16.4%, P<0.001), prior cerebral infarction (19.6% vs. 1.4%, P<0.001), and fasting glucose (6.09 vs. 5.20 mmol/L, P<0.001) versus non-CAD. PCSK9 levels were elevated in MVD (232.58±52.68 vs. 192.57±48.15 ng/mL, P<0.001), independently predicting MVD (OR=1.012, 95% CI:1.006–1.018, P<0.001). 2. PCSK9 correlated positively with NLRP3 (r=0.501), TLR4 (r=0.462), IL-1β (r=0.402), and IL-18 (r=0.426) (all P<0.001), but not with anatomical/functional stenosis indices (P>0.05). 3. Pre-PCI PCSK9 predicted post-procedural AMR (r=0.569, P<0.001), with ROC-AUC=0.841 (95% CI:0.747–0.936) at cutoff 231.98 ng/mL (sensitivity 86.7%, specificity 74.4%). 4. Post-treatment NLRP3 decreased in the intervention group (207.45±45.05 vs. 265.19±61.28 ng/mL, P<0.001) but increased in controls (277.12±53.27 vs. 252.20±59.88 pg/mL, P=0.010). PCSK9 reduction in the intervention group (223.50±40.34 vs. 234.18±44.95 ng/mL, P=0.073) was lower than controls (223.50±40.34 vs. 256.97±44.99 ng/mL, P=0.002). Conclusions 1. PCSK9 independently predicts MVD and correlates with NLRP3 inflammasome activation, emphasizing inflammatory pathways in MVD progression. 2. Pre-PCI PCSK9 predicts post-procedural CMD, enabling non-invasive risk stratification. 3. Probucol reduces NLRP3 and mitigates PCSK9 elevation, suggesting anti-inflammatory effects via inflammasome modulation. Combining PCSK9 inhibitors with anti-inflammatory agents may optimize MVD therapy.