Nuclear Methods for Immune Cell Imaging: Bridging Molecular Imaging and Individualized Medicine

Abstract

Inflammation is a key mechanistic contributor to the progression of cardiovascular disease, from atherosclerosis through ischemic injury and overt heart failure. Recent evidence has identified specific roles of immune cell subpopulations in cardiac pathogenesis that diverges between individual patients. Nuclear imaging approaches facilitate noninvasive and serial quantification of inflammation severity, offering the opportunity to predict eventual outcome, stratify patient risk, and guide novel targeted molecular therapies against specific leukocyte subpopulations. Here, we will discuss the established and emerging nuclear imaging methods to label and track exogenous and endogenous immune cells, with a particular focus on clinical situations in which targeted molecular inflammation imaging would be advantageous. The expanding options for imaging inflammation provide the foundation to bridge between molecular imaging and individual therapy.

Keywords: heart failure; inflammation; magnetic resonance imaging; myocardial infarction; positron emission tomography.

Figure 1.. Schematic overview of nuclear methods for immune cell labeling.

(A) exogenous ex vivo cell labeling. (B) endogenous in vivo cell imaging. (Created with BioRender.com)

Figure 2.. PET imaging of immune cells in animal models of AMI.

⁶⁸Ga-Pentixafor PET images showing prognostic value of CXCR4 expression. (A) Sample cardiac short-axis (SA) PET images at 3d after MI of a surviving mouse and a mouse dying early of left ventricular (LV) rupture. (B) ⁶⁸Ga-Pentixafor uptake within the infarct of surviving and LV rupture mice. (C) Correlation of ⁶⁸Ga-pentixafor signal to the left ventricular ejection fraction (LVEF) at 6 weeks on univariate analysis (modified from). PET/CT images of ⁶⁸Ga-DOTA-ECL1i at d3 (D) and ⁶⁴Cu-DOTA-ECL1i at d4 (E) after MI show comparable uptake (F) in the infarcted region of the same mouse. (reproduced from) (G) Correlation between ⁶⁸Ga-DOTA-ECL1i heart uptake at d4 and LVEF and akinetic area measured on d28 after MI (reproduced from). ¹⁸F-LW223 PET with BP_TC quantification detects macrophage-driven inflammation within heart 7d after MI without need for additional perfusion scan. Representative K₁ (H) and BP_TC images (I) of LV of MI rat demonstrating true TSPO signal across heart. (J) BP_TC values across global heart and LV anterior wall demonstrating TSPO expression within infarct (reproduced from). K₁: rate constant for transfer from arterial plasma to tissues; BP_TC:binding potential for impaired radiotracer transfer from plasma to tissue; A: anterior; P: posterior

Figure 3.. PET imaging of immune cells in animal models of pressure overload (A), myocarditis (B), and cardiomyopathy (C).

(A) CXCR4 PET defines diffuse myocardial inflammation after pressure-overload. (left) Representative ⁶⁸Ga-pentixafor and ¹⁸F-FDG images in sham and mice after transverse aortic constriction (TAC). (right) Comparison of ⁶⁸Ga-pentixafor (red) uptake after TAC with sham (black). (reproduced from) (B) ¹⁸F-FDG and ¹⁸F-FOL PET images in rat with autoimmune myocarditis. PET images show focal ¹⁸F-FOL uptake (arrows) in posterior LV wall. (modified from) (C) CCR2 and CCR5 PET/CT showed detection of cardiac macrophages in a mouse model of dilated cardiomyopathy. (reproduced from) Tnnt2: Troponin T2

Figure 4.. Molecular imaging of inflammation after AMI.

(A) CXCR4 PET 3d after lateral wall ST-elevation MI with low (left) or high signal (right). (B) Intensity of the early CXCR4 signal correlates LVEF at time of imaging and at 7±3 months follow-up (modified from).

Figure 5.. Imaging of inflammation in cardiac sarcoidosis.

Whole body and cardiac distribution of ¹⁸F-FDG in sarcoidosis displays focal patchy pattern of uptake in left ventricle on transaxial PET/CT images (lower panel). Patient preparation with no carbohydrate high fat diet and heparin administration suppressed myocardial ¹⁸F-FDG uptake to facilitate immune cell visualization.

Figure 6.. Clinical imaging of inflammation in valvular disease.

(A) Focal abnormal ¹⁸F-FDG accumulation identified around the aortic prosthetic valve (middle) despite no abnormality on computed tomographic angiography (CTA, left) or open surgical exploration (right). (B) Subsequent CTA revealed mycotic aneurysm (left) and transesophogeal echocardiography identified abscess formation (middle). Severe infection was confirmed with follow-up surgical exploration (right) (Reproduced from). RCA: right coronary artery; LCA: left coronary artery; PHV: prosthetic heart valve