Multiparametric Imaging of Organ System Interfaces

Abstract

Cardiovascular diseases are a consequence of genetic and environmental risk factors that together generate arterial wall and cardiac pathologies. Blood vessels connect multiple systems throughout the entire body and allow organs to interact via circulating messengers. These same interactions facilitate nervous and metabolic system's influence on cardiovascular health. Multiparametric imaging offers the opportunity to study these interfacing systems' distinct processes, to quantify their interactions, and to explore how these contribute to cardiovascular disease. Noninvasive multiparametric imaging techniques are emerging tools that can further our understanding of this complex and dynamic interplay. Positron emission tomography/magnetic resonance imaging and multichannel optical imaging are particularly promising because they can simultaneously sample multiple biomarkers. Preclinical multiparametric diagnostics could help discover clinically relevant biomarker combinations pivotal for understanding cardiovascular disease. Interfacing systems important to cardiovascular disease include the immune, nervous, and hematopoietic systems. These systems connect with classical cardiovascular organs, such as the heart and vasculature, and with the brain. The dynamic interplay between these systems and organs enables processes, such as hemostasis, inflammation, angiogenesis, matrix remodeling, metabolism, and fibrosis. As the opportunities provided by imaging expand, mapping interconnected systems will help us decipher the complexity of cardiovascular disease and monitor novel therapeutic strategies.

Keywords: biomarkers; brain; cardiovascular diseases; hematopoietic system; systems biology.

Figure 1

Immune-cardiovascular, hematopoietic and nervous system interactions forming a circuit in cardiovascular disease.

Figure 2

(A) Intravital imaging of structure and function in the beating heart at cellular resolution. From Vinegoni et al.. (B) Serial intravital microscopy of increased hematopoietic stem cells (HSC), sorted and labeled ex vivo with DiD (1,1′-dioctadecyl-3,3,3′,3′-tetramethylindodicarbocyanine perchlorate) fluorescent dye, reporting on their expansion in the bone marrow of mice with stroke. Serial intravital microscopy of the mouse calvarium 1 day before and 3 days after transient middle cerebral artery occlusion (tMCAO). Blue color represents the fluorescence signal produced by the bone imaging agent Osteosense-750; the fluorescence lectin signal stained blood vessels in red. DiD-labeled HSC are shown in white. From Courties et al.. (C) Intravital microscopy of macrophages egressing the spleen after MI. From Swirski et al.. (D) Triggered intravital multiphoton imaging of an atherosclerotic artery. Maximum intensity Z projections of the 3D movie of live CX3CR1^GFP Cd11c^YFP atherosclerotic apolipoprotein E knock out (ApoE^−/− ) mouse. Green—GFP+ cells; orange—YFP+ cells and blue—collagen. From McArdle et al..

Figure 3

Longitudinal polyglucose nanoparticle Macroflor optical and PET/MR imaging to non-invasively monitor macrophage biology in cardiovascular disease. (A) Intravital dynamic confocal microscopy of Macrolite taken up by cardiac macrophages in a CX3CR1^GFP reporter mouse. Green GFP signal indicates cardiac macrophages and red VT680 signals designates Macrolite. The 0 minute image was acquired prior to fluorescent probe injection into the tail vein. Intravascular signal was detected 2 minutes later, while the 30 minute time point illustrates co-localized Macrolite and GFP+ macrophages with (B) a higher magnification image co-localizaling Macroflor and macrophage signals. (C) Dual channel macrophage PET/MRI in ischemic heart disease shows macrophages and myeloperoxidase on (C) days 2 and (D) 6 post MI. White dotted line on PET/MRI outlines myocardium. Yellow dashed line on MRI outlines the infarct as identified by gadolinium enhancement and wall motion abnormality in cine loops. (E) In vivo PET standard uptake value (SUV) in infarct zone on days 2 and 6 post MI. (F) In vivo MRI contrast to noise ratio (CNR) in infarct 90 min after IV myeloperoxidase -Gd injection. From Keliher et al..

Figure 4

Multi-organ PET/MRI of the inflammatory tissue response after myocardial infarction (MI). (A) Representative multiparametric cardiac magnetic resonance (CMR) and PET images in a patient early after MI and reperfusion. The anteroseptal infarct region is highlighted by gadolinium contrast late enhancement (Gd LE; top row) and shows transmural tissue damage (bright) and subendocardial no reflow (black). Transmural edema (bright) on T2-weighted images (second row) exceeded the LE area. PET perfusion images (third row) showed perfusion defects in the infarct area with LE (late Gd enhanced). Also, ¹⁸F-deoxyglucose (FDG) uptake is present in the infarct region even when myocyte uptake is suppressed by heparin, a result that is consistent with regional inflammation (bottom row).(B) Multiorgan positron emission tomography (PET)-computed tomography (CT) analysis of glucose utilization. PET images (right) and hybrid PET/CT images (left) of the cardiac region, show the positioning of regions of interest for quantitative analysis of glucose use in the heart and lymphoid tissue. From Tim Wollenweber et al..

Figure 5

Imaging macrophage and hematopoietic progenitor proliferation in atherosclerosis. (A) 18F-fluorothymidine (FLT) PET uptake in mice with atherosclerosis. PET/CT images show higher 18F-FLT uptake in atherosclerotic lesions (arrow) of ascending aorta in an apolipoprotein E knock out (ApoE^−/−) compared with a wild-type (WT) mouse. High 18F-FLT signal is also present in the sternum and vertebrae (arrow heads) and gallbladder (asterisk). (B) Increased 18F-FLT uptake in bone marrow and spleen of ApoE^−/− mice compared with wild-type (WT). 18F-FLT and 18F-FDG PET/CT in humans with atherosclerosis. Sagittal image demonstrates extensive calcification in the aorta and carotid artery (arrows). 18F-FDG and 18F-FLT images show PET tracer uptake in the vessel wall of the aortic arch (arrows). From Ye et al..

Figure 6

Emotional stress, measured by the metabolic rate of resting amygdalae activity, predicted cardiovascular events. Increased ¹⁸F-fluorodeoxyglucose (FDG) uptake in the amygdala, bone marrow and arterial wall (aorta) in a subject who experienced an ischemic stroke during the follow-up period (right) vs. a subject who did not (left). From Tawakol et al.