The study protocol is a single-arm, open label pilot study designed to evaluate the impact of PCSK-9 inhibition on coronary blood flow in patients with stable coronary artery disease. Patients with stable coronary artery disease will be recruited from the BWH Cardiovascular Medicine clinic and/or from the BWH Nuclear Cardiology Laboratory. A target sample size of 50 participants will undergo imaging with N-13 ammonia or Rubidium-82 positron emission tomography (PET) and coronary computed tomography angiography (CCTA) before and after 12 months of PCSK-9 inhibition with Evolocumab to assess changes in myocardial blood flow, and plaque volume. To help account for physiological changes that may occur in myocardial blood flow and inflammatory biomarkers during the study period, we will also recruit a parallel control group of stable CAD patients who will undergo similar baseline and 12-month imaging and biomarker assessment. We plan to recruit 15 patients in the parallel control group.

The investigators propose an open-label investigator-initiated trial to directly test whether PCSK-9 inhibition with Evolocumab in patients with stable CAD improves PET CFR and stress MBF. To further elucidate the possible mechanisms by which myocardial blood flow improves with PCSK-9 inhibition, the investigators will assess changes in inflammatory biomarkers. The findings of this translational study will provide a physiological read-out of the comprehensive effects of Evolocumab on tissue perfusion and microvascular function in a high-risk population. As such, these data would serve to provide a mechanistic explanation for why Evolocumab may reduce cardiovascular events beyond a reduction in plaque burden and composition.

The central hypothesis of this study is that PCSK-9 inhibition will quantitatively improve myocardial blood flow as measured by positron emission tomography (PET) in patients with stable coronary artery disease. The investigators postulate that the improvement in myocardial blood flow will correlate with a reduction in inflammatory biomarkers, and not simply an improvement in coronary epicardial plaque burden.

Intervention Group:

Inclusion Criteria:

• Age: ≥ 50 (men) or ≥ 55 (women)

• Low-density lipoprotein cholesterol (LDL-C) ≥ 70 mg/dL

• Stable coronary artery disease (without plan to undergo revascularization before randomization) defined as one or more of the following:

  1. Abnormal nuclear perfusion imaging

     1. At least moderate ischemia involving >10% of the LV myocardium or
     2. Global coronary flow reserve (CFR) <1.8 or
     3. Stress myocardial blood flow (MBF) <1.8

  2. Abnormal coronary angiography (invasive coronary angiography or coronary computed tomography)

     1. ≥ 50% stenosis in ≥ 2 coronary vessels or
     2. Diffuse atherosclerosis in a 3-vessel distribution

  3. Elevated coronary calcium score

     1. CAC >100 + >1 ASCVD risk factor
     2. CAC >300

• If the patient is on a statin they must be on a stable dose for at least 3 months prior to enrollment.

Exclusion Criteria:

• History of myocardial infarction or stroke
• CABG < 3 months prior to screening
• Homozygous familial hypercholesterolemia
• History of cardiac transplantation
• LV ejection fraction < 40% or New York Heart Failure Association (NYHA) class III-IV for angina and/or dyspnea.
• History of infiltrative or hypertrophic cardiomyopathy
• Severe valvular disease
• Uncontrolled or recurrent ventricular tachycardia
• Fasting triglycerides > 500 mg/dL
• GFR ˂ 30 mL/min/1.73 m²
• Current use of a PCSK-9 inhibitor
• Currently pregnant or breastfeeding
• Contraindication to receive vasodilator agent
• Latex allergy

Parallel Control Group:

Patients will be invited to participate in the parallel control group if they meet study criteria, but 1) have a latex allergy and cannot use the Evolocumab autoinjector 2) LDL-C is just below the enrollment criteria (LDL 60-69), or 3) meet study criteria but prefer to not take an injectable medication at this time.