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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.

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

Background PCSK9 inhibition has emerged as a potent pharmaceutical approach to lowering LDL cholesterol (LDL-C). Monoclonal anti-PCSK9 antibodies have been shown in recent clinical trials to reduce cardiovascular events in patients with atherosclerotic cardiovascular disease, but the underlying mechanisms are not fully understood. Meanwhile, circulatory inflammation markers were not reduced with PCSK9 inhibitors, thus their effects on plaque inflammation remain elusive. Vessel wall imaging with magnetic resonance (VW-MRI) has enabled serial monitoring of changes in carotid plaque lipid content and inflammation noninvasively that correlates with coronary and carotid vascular events. Purpose Using serial VW-MRI, we studied the effects and time course of PCSK9 inhibition with alirocumab on carotid plaque lipid content and inflammation. Methods Patients with LDL-C ≥70 mg/dl on ≤70 mg per week atorvastatin or an equivalent (due to statin intolerance or treating-physician discretion) and soft carotid plaque(s) identified on ultrasound underwent carotid VW-MRI. Those with confirmed lipid-rich plaque(s) on VW-MRI received alirocumab (150 mg subcutaneously every other week) and were re-scanned at 3, 6, and 12 months after treatment. Carotid VW-MRI included pre- and post-contrast images for measuring percent lipid-rich necrotic core volume (%LRNC) and dynamic contrast-enhanced images for measuring the extravasation rate of gadolinium contrast (Ktrans, reflecting tissue blood flow, endothelial surface area, and microvessel permeability), a marker of plaque inflammation. The co-primary endpoints were changes in %LRNC and Ktrans at 12 months from baseline. Results Of 31 patients enrolled, 27 completed the study (mean age: 69±9; male: 67%; on statins and/or ezetimibe: 41%; median LDL-C: 120 mg/dl [interquartile range: 99, 158]). Alirocumab induced a 59% reduction in LDL-C (p Conclusions Serial VW-MRI documented plaque-stabilizing effects of PCSK9 inhibition with alirocumab, including plaque delipidation and attenuation of plaque inflammation. The reduction in plaque lipid content was apparent as early as 3 months. The reduction in Ktrans was not seen until 12 months of treatment and may indicate a later effect on microvascular structure and/or function. This observation represents the earliest time course of plaque morphology modification by non-statin therapy reported to date. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): The study was funded by an investigator-initiated grant from Regeneron and Sanofi.

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 (K

Background Global cardiovascular risk scores frequently underestimate risk in persons with underlying asymptomatic cardiac lesions who eventually experience cardiovascular events. The Get-With-The-Guidelines Initiative analysis revealed that over 70% of patients with a first cardiac event were well within guideline targets for lipid values. Most artery flow-disrupting events occur at locations with less than 50% lumen narrowing. From clinical studies published in the late 1990s using IVUS (in-the-artery-ultrasound) to visualize disease status, the typical heart attack occurs at locations with about 20% stenosis (narrowing), prior to sudden lumen closure and resulting ACS. This sudden lumen closure is caused by rupture of an unstable cardiac lesion causing a blood clot and occlusion in up to 75% of heart attacks. The role of multi-biomarker algorithms to identify vulnerable patients with these lesions at risk of short-term ACS events is of great interest. Methods We studied 725 adults (≥18 yrs) from Cardiology practices who received a 5-year modified Framingham Risk Score (mFRS), and a coronary artery disease predictive algorithm (CADPA) multi-biomarker score. CADPA incorporates 9 biomarkers (CTACK, Eotaxin, Fas Ligand, HGF, IL-16, MCP-3, sFas, HDL, and HbA1c) with age, sex, diabetes, and family history of myocardial infarction, previously shown to more accurately reclassify risk of cardiovascular events (cNRI=43%). Patients were classified into low ( Results Persons at low, intermediate, and high global risk categories were successively more likely to demonstrate high-risk scores with CADPA (Figure). However, 349 (65%) in the low mFRS risk group were reclassified into higher CADPA risk groups and 104 (70%) intermediate risk patients were reclassified into the high-risk group (p CADPA Risk Reclassification Conclusions We conclude that this novel multi-biomarker panel (CADPA) identifies many persons at increased risk of cardiac events due to asymptomatic cardiac lesions missed by traditional global risk methods. Further investigation of the value of such a test for prediction of near-term CVD events is required.

Acute Coronary Syndromes (ACS) are caused by free-radical mediated endothelial injury. Soft unstable coronary artery wall lesions form that can rupture causing thrombosis and obstruction. Three software systems (Akaike, Bayesian, Drop-in Deviance) tested 45 biomarkers and global risk factors to predict risk of ACS. A novel 9 protein algorithm was developed in 3 unique longitudinal, outcome-based studies and independently verified in MESA (Multiethnic Study of Atherosclerosis). The proteins selected include CTACK (Cutaneous T-Cell Attracting Chemokine)-homing of memory t-cells to tissue injury site; EOTAXIN (Eosinophil Chemotactic Protein)-attracts eosinophils to endothelial injury facilitating fibrin removal; MCP-3 (Monocyte Chemotactic Protein 3)-attracts monocytes and modulates activity; IL-16 (cytokine)-chemoattractant and modulator of T cell activation; sFAS (soluble FAS Ligand)-suppresses apoptosis; FAS Ligand (transmembrane protein tumor necrosis factor family member) induces apoptosis; HGF (Hepatocyte Growth Factor)-acts on epithelial cells and endothelial cells for angiogenesis, tumorogenesis, and tissue regeneration/repair; HDL (High-density Lipoprotein)-reverse cholesterol transport and inhibits oxidation, inflammation, endothelial activation, coagulation, and platelet aggregation; HbA1c (Hemoglobin A1c)-three-month average plasma glucose concentration. We conclude that the selection of biomarkers associated with endothelial damage and immune system response correlates with risk of ACS and reflects the underlying pathophysiology. Further studies are warranted.