Abstract 4139715: The impact of CSL112 and atorvastatin on lipid core stiffness in murine atherosclerotic plaques

Background: Plaque structural stress (PSS) is the stress within the body of atherosclerotic plaques, resulting from the dilation and stretching of vessels due to arterial pressure. Plaque rupture often occurs at sites of elevated PSS, especially when the stress level exceeds the mechanical strength of the plaque. Notably, a significant difference in stiffness between the softer lipid core and the stiffer fibrous cap significantly increases PSS. By increasing the elastic modulus (a measure of material stiffness) of lipid cores and thus reducing the stiffness disparity between plaque components, it may be possible to transition vulnerable plaques from a state of instability to stability. Hypothesis: Both CSL112, a human plasma-derived apolipoprotein A-I formulation that enhances reverse cholesterol transport, and atorvastatin increase the stiffness of plaque lipid cores. Methods: Rupture-prone atherosclerotic plaques were induced in 47 ApoE knockout male mice using a carotid tandem stenosis model after a 7-week high-fat diet. After surgery, mice were treated with either CSL112 (100 mg/kg) intravenously twice weekly (n=15), saline intravenously (n=15), or atorvastatin (10 mg/kg) daily by gavage for 5 weeks (n=17). All animals were euthanized at 20 weeks of age. Multiple sections from the first proximal segment of the right common carotid artery were extracted for stiffness measurements and adjacent tissues were sliced for histological examination to identify lipid cores. Using atomic force microscopy, nano-indentation tests were conducted on the lipid-rich regions of plaque samples, and the elastic moduli were determined by fitting the Hertzian contact model to the force-indentation data. Measurements were conducted in a blinded manner with respect to treatment groups. Results: The CSL112 group had the highest lipid stiffness, with a mean elastic modulus of 5.27 kPa (95% CI [4.74, 5.80]), followed by the atorvastatin group at 3.02 kPa (95% CI [2.51, 3.53]), and the saline group at 2.11 kPa (95% CI [1.54, 2.68]). Statistical analysis indicated that CSL112 significantly increased the elastic modulus of lipid cores compared to both atorvastatin and saline (p <0.001), while lipid stiffness was also significantly higher in the atorvastatin group compared to saline (p = 0.039). Conclusion: The increase in lipid pool stiffness within atherosclerotic plaques treated with CSL112 and atorvastatin may reduce the level of PSS and enhance plaque structural stability.