Immunomodulatory Effects of PCSK9 Inhibition

Cardiovascular disease (CVD) represents the leading cause of death worldwide. While medications, such as statins, significantly reduce atherosclerotic CVD (ASCVD) risk by lowering low density lipoprotein levels, they may also have pleiotropic effects on inflammation. The immunomodulatory effects of these medications are relevant to ASCVD risk reduction given that inflammation plays a central role in atherosclerotic plaque formation (atherogenesis) and influences the development of vulnerable plaque morphology. Patients on statins, however, may have residual inflammation contributing to incident ASCVD despite the potent LDL-lowering effects of statins. While new therapies, such as proprotein convertase subtilisin/kexin type 9 (PSCK9) inhibitors, further reduce incident ASCVD and drastically reduce LDL-C below that achieved by statin therapy alone, PCSK9 inhibitors may also have pleiotropic effects on inflammation. Thus, PCSK9 inhibitors may help reduce arterial inflammation to a level closer to that of patients without ASCVD. This study will apply a novel targeted molecular imaging approach, technetium 99m (99mTc)-tilmanocept SPECT/CT, to determine if residual macrophage-specific arterial inflammation is present with statin therapy and the immunomodulatory effects of PSCK9 inhibition. Given the continued high mortality and morbidity attributable to ASCVD, strong imperatives exist to better understand the immunomodulatory effects of lipid lowering therapies and residual inflammatory risk. This understanding, in turn, will inform the development of new ASCVD preventative and treatment strategies as well as elucidate other indications for established therapies.

Inclusion Criteria:18 to 85 years of ageCASE PARTICIPANTS ONLY: History of ASCVD (including a history of coronary artery disease, carotid artery disease, peripheral artery disease, acute coronary syndrome, percutaneous coronary intervention, coronary bypass surgery, carotid endarterectomy, stroke or TIA)CASE PARTICIPANTS ONLY: High-intensity statin therapy for at least 6 months prior enrollment and without an interruption of >1 monthCASE PARTICIPANTS ONLY: initiation of PCSK9 inhibition with either evolocumab or alirocumab (and not inclisiran - PSCK9 inhibition through small interfering RNA51)Exclusion Criteria:pregnancy or breastfeedingCONTROL PARTICIPANTS ONLY: No history of ASCVD (including a history of coronary artery disease, carotid artery disease, peripheral artery disease, acute coronary syndrome, percutaneous coronary intervention, coronary bypass surgery, carotid endarterectomy, stroke or transient ischemic attack [TIA])current treatment with prescription, systemic (oral, IV, or IM) steroids or anti-inflammatory/immune suppressant medical therapies (excluding topical therapies, UV therapy, ASA-derivative therapies, or NSAIDS) for autoimmune/inflammatory diseases (psoriasis, rheumatoid arthritis, inflammatory bowel disease, lupus), post-transplant care, asthma, or pain syndromesuse of oral steroids or prescription oral anti-inflammatory/immune suppressant medication for > 7 days within the past 1 monthuse of IV or IM steroids or IV or IM anti-inflammatory/immune suppressant medication within the past 3 monthsCONTROL PARTICIPANTS ONLY: use of statin therapy within the past 6 monthsknown allergy to dextrans and/or DTPA (diethylenetriamine pentaacetate) and/or radiometalseGFR (glomerular filtration rate) < 60 ml/min/1.73 m2 calculated by chronic kidney disease (CKD)-EPI (epidemiology collaboration) calculatorknown severe allergy to iodinated contrast mediaany of the following contraindications to nitroglycerin:known narrow angle glaucomachronic hypotension requiring medical therapyknown severe aortic stenosisuse of phosphodiesterase type 5 inhibitor (e.g. sildenafil, tadalafil, vardenafil) AND self-reported inability/refusal to abstain from use of these medications within the 5 days prior to scheduled cardiac CT angiography (CCTA) scansignificant radiation exposure (>2 CT angiograms) received within the past 12 monthsconcurrent enrollment in another research study judged by the study investigators to interfere with the current study