The advancing clinical impact of molecular imaging in CVD

Abstract

Molecular imaging seeks to unravel critical molecular and cellular events in living subjects by providing complementary biological information to current structural clinical imaging modalities. In recent years, molecular imaging efforts have marched forward into the clinical cardiovascular arena, and are now actively illuminating new biology in a broad range of conditions, including atherosclerosis, myocardial infarction, thrombosis, vasculitis, aneurysm, cardiomyopathy, and valvular disease. Development of novel molecular imaging reporters is occurring for many clinical cardiovascular imaging modalities (positron emission tomography, single-photon emission computed tomography, magnetic resonance imaging), as well as in translational platforms such as intravascular fluorescence imaging. The ability to image, track, and quantify molecular biomarkers in organs not routinely amenable to biopsy (e.g., the heart and vasculature) open new clinical opportunities to tailor therapeutics based on a cardiovascular disease molecular profile. In addition, molecular imaging is playing an increasing role in atherosclerosis drug development in phase II clinical trials. Here, we present state-of-the-art clinical cardiovascular molecular imaging strategies, and explore promising translational approaches positioned for clinical testing in the near term.

Keywords: (158)Gd-ESMA; (18)F-fluorodeoxyglucose; (18)F-sodium fluoride; AS; AT1R; CAC; CEA; CMR; CT; DVT; FDA; FDG; Food and Drug Administration; ICG; LDL; LV; MI; MMP; MRI; NIRF; NaF; OFDI; OTW; PC; PET; RAAS; SUV; TBR; USPIO; aneurysm; angiotensin II type 1 receptor; aortic stenosis; atherosclerosis; cardiac magnetic resonance; carotid endarterectomy; computed tomography; coronary artery calcium; deep vein thrombosis; gadolinium-labeled elastin-specific magnetic resonance contrast agent; heart failure; high-sensitivity C-reactive protein; hsCRP; indocyanine green; left ventricle/ventricular; low-density lipoprotein; magnetic resonance imaging; matrix metalloproteinase; molecular imaging; myocardial infarction; near-infrared fluorescence; optical frequency domain imaging; over-the-wire; perfusion catheter; positron emission tomography; renin-angiotensin-aldosterone system; standardized uptake value; target-to-background ratio; thrombosis; ultrasmall superparamagnetic particles of iron oxide; valvular disease; vascular injury.

Figure 1. Periodontal FDG-PET

PET (top, right) and PET-CT fusion (top, left) images reveal high FDG uptake in periodontal tissues (boxes indicate measurement regions). Quantitative TBR of periodontal FDG activity significantly correlated with carotid FDG uptake. Reproduced with permission from (6).

Figure 2. Effect of pioglitazone and glimepiride on atherosclerotic plaque FDG uptake

FDG PET-CT images from representative patients treated at baseline (left) or following 4 months treatment (right) with pioglitazone or glimepiride. Arrows indicate an area of reduced FDG uptake in the pioglitazone arm. Reproduced with permission from (8).

Figure 3. Coronary artery 18F-sodium fluoride (NaF) PET/CT imaging

(A) A control group patient with absent coronary artery calcium and no coronary NaF PET activity. Note the significant vertebral body NaF uptake. (B) Despite extensive left anterior descending (LAD) calcification, coronary NaF signal is not present in this subject. (C, D) Examples of patients with significant NaF PET activity and CT coronary calcification in the proximal and mid LAD. (E) Heightened NaF coronary PET uptake in the culprit proximal right coronary artery (RCA) of a patient after recent inferior non-ST elevation myocardial infarction. Note the absence of LAD NaF PET signal. (F) Coronary angiography in the patient from (E) demonstrated an ulcerated, thrombotic proximal RCA lesion. Reproduced with permission from (15).

Figure 4. Intravascular NIRF imaging of protease inflammation in experimental atherosclerosis

(A, B) Fluoroscopic and angiographic images (A, yellow dotted lines: high magnification inset of the radiopaque tip of the catheter; B, solid yellow line: intravascular catheter tip position) positioned in the rabbit aorta, proximal to the iliac bifurcation. (C) Co-registered longitudinal IVUS demonstrates mild aortic plaques P1 and P2. (D) NIRF catheter pullback aligned with images A through C reveals NIRF protease activity at mild plaques (top) with 1-dimensional angle-averaged NIRF plot (bottom). (E) Superimposed longitudinal IVUS and NIRF fusion images (NIRF scale bar: yellow/white=strong, red/black=weak). (F, G) Longitudinal and (H, I) axial images of plaques P1 and P2. Reproduced with permission from (18).

Figure 5. Elastin-targeted MRI of murine atherosclerotic plaque remodeling with ¹⁵⁸Gd-ESMA

(a) ¹⁵⁸Gd-ESMA chemical structure and formula. (b) ApoE^−/− mouse brachiocephalic cross-sectional time-of-flight (TOF) angiography alignment (red box) comparing baseline (precontrast) with high-resolution contrast MRI (Gd-DTPA), ¹⁵⁸Gd-ESMA, and TOF/dynamic contrast (fusion) images. Scale bars, 250 m. Reproduced with permission from (21).

Figure 6. Human myocardial angiotensin II receptor PET/CT imaging

Mid-cardiac PET/CT fusion images in a healthy volunteer obtained 1 hour after injection with the angiogensin II type I receptor ligand ¹¹C-KR31173. (Left) At baseline, ¹¹C-KR31173 signal localizes to the ventricular myocardium. (Right) 3 hours after administration of a single 40 mg PO dose of the angiotensin receptor blocker olmesartan, myocardial ¹¹C-KR31173 PET uptake is significantly reduced. Reproduced with permission from (24).

Figure 7. MRI molecular imaging of inflammation in abdominal aortic aneurysm (AAA)

Representative color maps of T2-weighted MRI signal change (blue=low, red=high) induced by local accumulation of ultrasmall superparamagnetic particles of iron oxide (USPIO) in 3 patients with AAA. (A) A patient with enhanced periluminal T2 signal. (B) More diffuse, non-contiguous T2 changes present within the intraluminal thrombus, but not involving the aortic wall. (C) Periluminal T2 signal change with focal aortic T2 enhancement revealing USPIO accumulation and inflammation within the AAA wall. (D-E) T2-weighted MRI images without the superimposed color maps for comparison demonstrating focal T2 signal loss at USPIO-rich sites. Reproduced with permission from (32).

Figure 8. Clinical FDG PET imaging of inflammation in aortic stenosis

(A) CT-determined aortic valve calcification at differing AS severities. (B) Co-registered FDG PET/CT fusion demonstrates increased FDG valve uptake for mild and moderate AS (arrows), that diminishes for heavily calcified severe AS. Reproduced with permission from (34).