Regression in carotid plaque lipid content and neovasculature with PCSK9 inhibition: A time course study.

BACKGROUND AND AIMS: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors reduce cardiovascular events, but their effects on atherosclerotic plaque remain elusive. Using serial magnetic resonance imaging (MRI), we studied changes in carotid plaque lipid content and neovasculature under PCSK9 inhibition with alirocumab. METHODS: Among patients with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dl but ineligible for high-dose statin therapy, those with lipid core on carotid MRI were identified to receive alirocumab 150 mg every 2 weeks. Follow-up MRI was performed at 3, 6, and 12 months after treatment. Pre- and post-contrast MRI were acquired to measure percent lipid core volume (% lipid core). Dynamic contrast-enhanced MRI was acquired to measure the extravasation rate of gadolinium contrast (Ktrans), a marker of plaque neovasculature. RESULTS: Of 31 patients enrolled, 27 completed the study (mean age: 69 ± 9; male: 67%). From 9.8% at baseline, % lipid core was progressively reduced to 8.4% at 3 months, 7.5% at 6 months, and 7.2% at 12 months (p = 0.014 for trend), which was accompanied by a progressive increase in % fibrous tissue (p = 0.009) but not % calcification (p = 0.35). Ktrans was not reduced until 12 months (from 0.069 ± 0.019 min-1 to 0.058 ± 0.020 min-1; p = 0.029). Lumen and wall areas did not change significantly during the study period. CONCLUSIONS: Regression in plaque composition and neovasculature were observed under PCSK9 inhibition on carotid MRI, which provides unique insight into the biological process of plaque stabilization with disease-modifying therapies.

Serial magnetic resonance imaging detects a rapid reduction in plaque lipid content under PCSK9 inhibition with alirocumab.

PCSK9 inhibitors lower low-density lipoprotein cholesterol (LDL-C) and reduce cardiovascular events. The clinical benefits presumably result from favorable effects on atherosclerotic plaques. Lipid-core and plaque inflammation have been recognized as main determinants of risk for plaque rupture and cardiovascular events. Both can be noninvasively assessed with carotid MRI. We studied if PCSK9 inhibition with alirocumab induces regression in lipid-core or plaque inflammation within 6 months as measured by MRI. Patients with non-calcified carotid plaque(s) and baseline LDL-C ≥ 70 mg/dl, who were statin-intolerant or taking a low-dose statin (≤ 10 mg per day of atorvastatin or an equivalent), received subcutaneous alirocumab 150 mg every 2 weeks. Carotid MRI was performed at baseline and 6 months after treatment, including pre- and post-contrast images for measuring percent lipid-core volume (%LC) and dynamic contrast-enhanced images for measuring microvessel leakiness (Ktrans), a marker of inflammation. Twenty-eight patients completed the study (69 ± 9 years; 64% male). Alirocumab led to significant changes in LDL-C (p < 0.001) and high-density lipoprotein cholesterol (HDL-C) (p = 0.003). At 6 months, there was a significant reduction in %LC (mean: - 2.1% [- 3.5, - 0.7], p = 0.005; a 17% reduction from baseline of 9.9%) without significant changes in lumen/wall area or in the inflammatory index Ktrans. Carotid plaque lipid content was reduced by 17% after 6 months of PCSK9 inhibition with alirocumab. This was seen before observable changes in lumen or wall areas, which supports pursing plaque lipid content as a more sensitive marker of therapeutic response compared to lumen or wall areas in future technical developments and serial studies.