PCSK9 expression in fibrous cap possesses a marker for rupture in advanced plaque.

BACKGROUND: To date, PCSK9 inhibitors are well known for eliminating cardiac and cerebral artery ischemia events by lowering the serum lipid level. However, the pathophysiological value of in-plaque PCSK9 expression is still unclear. METHODS: Advanced plaques removed by carotid endarterectomy were sectioned and stained to identify the PCSK9 expression pattern and its co-expression with rupture-relevant markers. To investigate the correlation of PCSK9 expression with regional blood shear flow, hemodynamic characteristics were analyzed using computational fluid dynamics, and representative parameters were compared between PCSK9 positive and negative staining plaques. To explore this phenomenon in vitro, human aortic vascular smooth muscle cells were used to overexpress and knock down PCSK9. The impacts of PCSK9 modulations on mechanical sensor activity were testified by western blot and immunofluorescence. Real-time polymerase chain reaction was used to evaluate the transcription levels of downstream rupture-prone effectors. RESULTS: PCSK9 distribution in plaque preferred cap and shoulder regions, residing predominantly in smooth muscle actin-positive cells. Cap PCSK9 expression correlated with fibrous cap thickness negatively and co-expressed with MMP-9, both pointing to the direction of plaque rupture. A hemodynamic profile indicated a rupture-prone feature of cap PCSK9 expression. In vitro, overexpression and knockdown of PCSK9 in human aortic vascular smooth muscle cells has positive modulation on mechanical sensor Yes-associated protein 1 (YAP) activity and transcription levels of its downstream rupture-prone effectors. Serial section staining verified in situ colocalization among PCSK9, YAP, and downstream effectors. CONCLUSIONS: Cap PCSK9 possesses a biomarker for rupture risk, and its modulation may lead to a novel biomechanical angle for plaque interventions.

Assessing rupture risk by hemodynamics, morphology and plasma concentrations of the soluble form of tyrosine kinase receptor Axl in unruptured intracranial aneurysms.

OBJECTIVE: This study investigated the relationship between morphology, hemodynamic parameters, and plasma concentrations of the soluble form of tyrosine kinase receptor Axl (sAxl) and their potential role in assessing the intracranial aneurysm rupture risk. METHODS: Thirty-nine patients were retrospectively recruited and these patients were divided into low and high rupture risk groups based on the PHASES score. Plasma levels of sAxl were measured using an enzyme-linked immunosorbent assay-based method. Computational fluid dynamics were used to calculate the morphological and hemodynamic parameters. Differences between clinical data, morphological-hemodynamic parameters and sAxl level were initially determined using univariate analysis. The variables (p ＜ 0.05) were included in a logistic regression model, and the specificity and sensitivity of the selected parameters were evaluated both graphically and statistically using receiver operating characteristic (ROC) curve methods. RESULTS: Aneurysm size ratio (p = 0.023), and normalized wall shear stress (WSS) (p = 0.02) showed significant differences between the two groups. Plasma concentrations of sAXL with a high rupture risk were significantly higher than the low rupture risk (8.47 ± 4.43 ng/ml vs. 5.37 ± 3.21 ng/ml; p = 0.016). Binary logistic regression analysis indicated that the concentration of sAxl was an independent determinant of high rupture risk (odds ratio=1.41, 95%CI=1.08-1.83, p = 0.011). The combination of sAxl + size ration (SR) + WSS achieved the highest area under the curve (0.849) for predicting rupture risk. CONCLUSIONS: Unruptured intracranial aneurysms with a higher rupture risk had a larger SR, lower WSS, and higher plasma sAxl concentration. Combining sAxl, SR, and WSS could help estimate the rupture risk of intracranial saccular aneurysm.