Immunomodulatory Effects of PCSK9 Inhibition

Study Overview
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Brief Summary
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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.

Official Title
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ImmuNomodulatory EffectS of PCSK9 Inhibition: A TaRgeted Molecular Imaging AppRoach

Conditions
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Atherosclerotic Cardiovascular Disease, Cardiovascular Diseases, Atherosclerosis, Arterial Inflammation

Intervention / Treatment
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* Other: Contrast-enhanced CCTA
* Other: 99mTc-tilmanocept SPECT/CT scanning


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 to 85 years of age CASE 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 month CASE PARTICIPANTS ONLY: initiation of PCSK9 inhibition with either evolocumab or alirocumab (and not inclisiran - PSCK9 inhibition through small interfering RNA51) Exclusion Criteria: pregnancy or breastfeeding CONTROL 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 syndromes use of oral steroids or prescription oral anti-inflammatory/immune suppressant medication for > 7 days within the past 1 month use of IV or IM steroids or IV or IM anti-inflammatory/immune suppressant medication within the past 3 months CONTROL PARTICIPANTS ONLY: use of statin therapy within the past 6 months known allergy to dextrans and/or DTPA (diethylenetriamine pentaacetate) and/or radiometals eGFR (glomerular filtration rate) < 60 ml/min/1.73 m2 calculated by chronic kidney disease (CKD)-EPI (epidemiology collaboration) calculator known severe allergy to iodinated contrast media any of the following contraindications to nitroglycerin: known narrow angle glaucoma chronic hypotension requiring medical therapy known severe aortic stenosis use 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) scan significant radiation exposure (>2 CT angiograms) received within the past 12 months concurrent enrollment in another research study judged by the study investigators to interfere with the current study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Case group: History of ASCVD, on high-intensity statins and initiating PCSK9 inhibitor therapy<br>History of ASCVD, on high-intensity statins and initiating PCSK9 inhibitor therapy | Other: Contrast-enhanced CCTA<br>* Allows for non-invasive assessment of atherosclerotic plaque burden and morphology<br>Other: 99mTc-tilmanocept SPECT/CT scanning<br>* 99mTc-Tilmanocept SPECT/CT allows for visualization of macrophage-specific arterial infiltration<br>|
| Control group: No history of ASCVD, not on statins or initiating PCSK9 inhibitor therapy<br>No history of ASCVD, not currently on high-intensity statins or initiating PCSK9 inhibitor therapy | Other: Contrast-enhanced CCTA<br>* Allows for non-invasive assessment of atherosclerotic plaque burden and morphology<br>Other: 99mTc-tilmanocept SPECT/CT scanning<br>* 99mTc-Tilmanocept SPECT/CT allows for visualization of macrophage-specific arterial infiltration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Between-group difference (case participants versus control participants) in percent volume with aortic 99mTc-tilmanocept across different uptake thresholds |  | Baseline | 
| Change in the percent volume with aortic 99mTc-tilmanocept uptake across different uptake thresholds after PCSK9 inhibitor therapy for 12 months (case participants only) |  | Baseline and 12 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relationship between baseline immune cell subpopulations (cells/µL) and aortic volume with 99mTc-tilmanocept uptake |  | Baseline and 12 Months | 
| Relationship between baseline markers of immune activation/ systemic inflammation and aortic volume with 99mTc-tilmanocept uptake |  | Baseline and 12 Months | 
| Relationship between change in macrophage-specific arterial infiltration with PCSK9 inhibitors and change in atherosclerotic plaque volume (mm3) |  | Baseline and 12 Months | 
| Relationship between change in macrophage-specific arterial infiltration with PCSK9 inhibitors and change in immune cell subpopulations (cells/µL) |  | Baseline and 12 Months | 
| Relationship between change in macrophage-specific arterial infiltration with PCSK9 inhibitors and change in markers of immune activation/ systemic inflammation |  | Baseline and 12 Months | 
| Relationship between change in macrophage-specific arterial infiltration with PCSK9 inhibitors and baseline atherosclerotic plaque volume (mm3) |  | Baseline and 12 Months | 
| Relationship between change in macrophage-specific arterial infiltration with PCSK9 inhibitors and baseline immune cell subpopulations (cells/µL) |  | Baseline and 12 Months | 
| Relationship between change in macrophage-specific arterial infiltration with PCSK9 inhibitors and baseline markers of immune activation/ systemic inflammation |  | Baseline and 12 Months |