Abstract
Growing evidence implicates the immune system as a critical mediator of cardiovascular disease progression and a viable therapeutic target. Increased inflammatory cell activity is seen in the full spectrum of disorders from early-stage atherosclerosis through myocardial infarction, cardiomyopathy, and chronic heart failure. Although therapeutic strategies to modulate inflammation have shown promise in preclinical animal models, efficacy in patients has been modest owing in part to the variable severity of inflammation across individuals. The diverse leukocyte subpopulations involved in different aspects of heart disease pose a challenge to effective therapy, wherein adverse and beneficial aspects of inflammation require appropriate balance. Noninvasive molecular imaging enables tissue-level interrogation of inflammatory cells in the heart and vasculature to provide mechanistic and temporal insights into disease progression. Although clinical imaging has relied on 18F-FDG as a nonselective and crude marker of inflammatory cell activity, new imaging probes targeting cell surface markers of different leukocyte subpopulations present the opportunity to visualize and quantify distinct phases of cardiac and vessel wall inflammation. Similarly, therapies are evolving to more effectively isolate adverse from beneficial cell populations. This parallel development of immunocardiology and molecular imaging provides the opportunity to refine treatments using imaging guidance, building toward mechanism-based precision medicine. Here, we discuss progress in molecular imaging of immune cells in cardiology from use of 18F-FDG in the past to the present expansion of the radiotracer arsenal and then to a future theranostic paradigm of tracer–therapy compound pairs with shared targets. We then highlight the critical experiments required to advance the field from preclinical concept to clinical reality.
Inflammation is a critical determinant of cardiac outcomes, underlying the complete spectrum of cardiovascular disease from atherosclerosis and acute coronary syndromes through chronic heart failure. Treatment strategies targeting the innate and adaptive immune system to improve cardiac outcomes have been successfully applied in animal models of disease and have shown promise in clinical application. The interplay between immune cells and the myocardium has stimulated the growth of the subspecialty of cardioimmunology, specifically addressing the role of the immune system in cardiovascular disease.
Conventional dogma identifies monocytes and derivative macrophages as central mediators of vascular and cardiac remodeling and classifies these cells into 2 categories: proinflammatory or reparative. These distinctions are based on in vitro macrophage behavior and response to specific cytokines, but the in vivo reality is more complex, with several phenotypically distinct subpopulations of macrophages having been identified (1). Cell-mapping studies of the adult human heart identify numerous myeloid and lymphoid cell populations in the myocardium, including macrophages, monocytes, and dendritic cells, as well B and T lymphocytes and natural killer cells, respectively (2). The relative proportions of these cell types change dramatically in the setting of cardiovascular disease, such that precise control of inflammation comprises an undertreated contributor to disease progression.
In atherosclerosis, inflammation is associated with unstable plaque and has been suggested as an indicator of patient vulnerability and risk for subsequent myocardial infarction or cerebral stroke (3). Moreover, ischemic injury to the myocardium instigates an immediate and robust inflammatory response characterized by extravasation of myeloid cells to the damaged region, where they initially perpetuate inflammation, recruit other immune cells, activate cardiac fibroblasts, and clear cellular debris (4). As the tissue microenvironment changes, the dominant immune cell populations also adapt, supporting inflammatory resolution, extracellular matrix reorganization, and angiogenesis to repair the injury (4). The intensity of inflammation after infarction is a marker of subsequent outcome. Heart failure is similarly characterized by increased inflammatory cell activity (5), though the precise interplay of leukocyte subpopulations remains equivocal. Other infiltrative diseases such as myocarditis and cardiac sarcoidosis also exhibit altered patterns of immune cell content in the heart (6), a potential avenue for image-based diagnostics and therapy.
In this review, we describe the growing relevance of imaging immune cells in the field of cardioimmunology. Specifically, we trace the parallel evolution of therapeutic and imaging approaches targeting the immune system in cardiovascular disease, from broad diagnostic evaluation using nonselective agents through novel radioligands targeting specific leukocyte subpopulations. We then explore the potential for molecular imaging to refine and optimize therapeutic approaches while defining the critical studies necessary to transform this theranostic concept into clinical reality.
THE PAST
First Experience with Antiinflammatory Therapy in Cardiovascular Disease
Although improvements in patient management, including timely revascularization, have reduced acute mortality after myocardial infarction, surviving patients are at increased risk of developing progressive heart failure (7). The extent and severity of inflammation after myocardial infarction is predictive of long-term outcome. Patients with an elevated blood leukocyte count have a higher incidence of cardiac events than those with lower white blood cell counts at the time of presentation (8). Serum biomarkers such as high-sensitivity C-reactive protein can provide useful population-based statistics (9) but are limited in the characterization of the local tissue microenvironment, which is relevant to disease progression. Based in part on these observations, antiinflammatory treatments have been applied in the postinfarction population, but despite promising preclinical observations, experience in clinical application has been mixed (9). Continuous delivery of glucocorticoids or nonsteroidal antiinflammatory drugs promotes infarct expansion and a higher risk of adverse cardiac events (9,10). Likewise, broad blockade of integrins to inhibit myeloid cell extravasation to the infarct territory is associated with ventricle rupture in mice and no improvement in clinical outcome (11,12). Inhibition of tumor necrosis factor α with etanercept similarly improved cardiac function in animal models but failed to reduce mortality and ventricle remodeling in clinical trials (13). Likewise, blockade of interleukin 6 signaling using the interleukin 6 receptor therapeutic monoclonal antibody tocilizumab suppressed inflammation in the heart and reduced ventricle remodeling in mice (14), as well as lowering high-sensitivity C-reactive protein and troponin T levels in patients over 3 d after ST-elevation myocardial infarction (15). More recently, follow-up studies indicated less microvascular obstruction but no difference in final infarct size (16). Application of cyclosporine, a potent immunomodulatory agent that inhibits T-cell activation, immediately before reperfusion therapy was expected to reduce infarct size by suppressing reperfusion injury (17), but results from a multicenter double-blind randomized trial showed no reduction of cardiac outcomes or adverse ventricle remodeling (18). Effectively, we have an incomplete understanding of the protective and adverse effects of cardiac immune cells, rendering cardiac inflammation a challenging therapeutic target. Moreover, it has remained difficult to monitor cardiac inflammation in vivo, hampering the ability to ascertain the optimal timing for delivery of these therapies.
Evolution of Radionuclide Inflammation Imaging
Conventional measurements of inflammation from blood provide some information on the systemic inflammatory state but do not effectively assess the extent and severity of inflammation at the site of injury, for example, after myocardial infarction. Noninvasive imaging overcomes this limitation, providing a quantitative readout of the cellular content at the tissue level. T2-weighted MRI can identify edema associated with inflammation but cannot directly distinguish the immune cell contribution to the altered signal. By contrast, PET imaging can directly visualize leukocytes in the tissue microenvironment, thereby providing a tangible link to the putative therapeutic target.
Clinical experience has traditionally relied on the enhanced glucose metabolism of inflammatory leukocytes, which leads to increased uptake of the glucose analog 18F-FDG in regions of inflammation. As such, 18F-FDG has been used across many cardiovascular disorders to quantify inflammatory cell content (Table 1). In peripheral arteries, this approach has allowed the identification of inflamed atherosclerotic plaque, which correlates with a higher incidence of major adverse cardiac events in follow-up clinical studies. Because of robust glucose uptake by cardiomyocytes, isolation of the inflammatory signal in coronary arteries or the injured myocardium is challenging, requiring careful suppression of glucose utilization by a combination of fasting, high fat loading, and heparin administration in patients or ketamine–xylazine anesthesia in rodents to promote fatty acid use by the heart (19,20). Nonetheless, 18F-FDG imaging provided valuable insights into the contribution of early inflammation to ventricle remodeling in cardiovascular disease. In mouse models of myocardial infarction, 18F-FDG uptake is temporally elevated in the first days after coronary artery ligation, proportional to increased numbers of proinflammatory Ly6Chigh monocytes in the infarct and border zone (20,21). Diffusely elevated 18F-FDG uptake throughout the myocardium is also observed in pressure overload heart failure, but unlike acute myocardial ischemia, tracer uptake does not correlate with total numbers of inflammatory cells in the left ventricle (22). This discrepancy reflects the major limitation of 18F-FDG as a marker of inflammation, namely the promiscuity of the cellular substrate, which includes not only monocytes and macrophages but also cardiomyocytes under stress. With proper suppression, however, the extent and intensity of 18F-FDG uptake in the infarct region in the first week after ST-elevation myocardial infarction independently predicted subsequent functional decline in patients (Fig. 1) (23,24). Inflammation in the myocardium is paralleled by increased 18F-FDG uptake in the spleen and bone marrow reflecting the systemic inflammatory state after acute myocardial infarction (25). 18F-FDG has been clinically valuable in infiltrative cardiomyopathies such as cardiac sarcoidosis, characterized by diverse leukocyte infiltration of the myocardium (26). Distinct patterns of 18F-FDG can identify detrimental leukocyte activity but remain dependent on effective suppression of the cardiomyocyte signal, a continued challenge to effective diagnosis.
Applications of 18F-FDG for Cardiovascular Inflammation Imaging
18F-FDG inflammation PET/CMR imaging in myocardial infarction. Sample short-axis image of patient after acute ST-elevation myocardial infarction demonstrates local accumulation of 18F-FDG in infarct region associated with increased extracellular volume due to immune cell content. ECV = extracellular volume; LBM = lean body mass. (Reprinted with permission of (24).)
Taken together, experience with 18F-FDG imaging provides a solid foundation for the potential of inflammation imaging to quantify immune cell activity in cardiovascular disease as a diagnostic and prognostic biomarker and to monitor therapeutic response. However, the ability to accurately isolate the inflammatory signal from the cardiomyocyte background, which is not static in disease conditions, remains a challenge. Moreover, the promiscuity of 18F-FDG binding across different inflammatory cells translates to an equivocal signal that may render it difficult to discern response to more selective antiinflammatory therapies that shift the proportions of adverse and beneficial leukocyte subpopulations.
THE PRESENT
Reevaluation of Antiinflammatory Therapy in Cardiovascular Disease
Characterization of immune cell dynamics in cardiovascular disease has allowed a refined approach to antiinflammatory therapy in these patients. Refined inhibition of upstream inflammatory cytokines provided confirmatory evidence of the role of inflammatory leukocytes in the progression of cardiovascular disease. Therapeutic antibody–mediated inhibition of interleukin 6 before coronary angiography lowered high-sensitivity C-reactive protein levels during the hospitalization period (15). Inhibition of interleukin 1β in patients with a previous myocardial infarction and elevated high-sensitivity C-reactive protein lowered the incidence of recurrent major cardiovascular events independently of changes in lipid levels (27). Application of colchicine to patients after acute myocardial infarction similarly reduced major adverse cardiac events, though the direct antiinflammatory effects of colchicine in coronary heart disease remain to be elucidated (28).
Taken together, the capacity to modulate specific components of the inflammatory cascade in cardiovascular disease is an appealing prospect. Further preclinical studies have suggested the value of targeting distinct cell populations to improve functional outcomes in cardiovascular disease. Refinement of specific cell populations involved in the process could facilitate precise modulation of the tissue microenvironment to promote repair and resolve adverse inflammation. However, inflammation remains an individually varied and challenging therapeutic target, since contributing cell populations are diverse and dynamically changing over the evolution of the disease. As such, the targeting and timing of therapy may be essential to its efficacy.
Clinical and Preclinical Use of Cardiovascular Inflammation Imaging
As therapeutic approaches have begun to target select cell populations, the imaging field has endeavored to develop more specific radioligands to better distinguish detrimental inflammation from the myocyte background (Table 2). In vitro studies have demonstrated a spectrum of affinity for distinct leukocyte subtypes for a range of radiopharmaceuticals (Fig. 2) (29). As multiomics platforms generate larger datasets, new imaging and therapeutic targets are emerging, providing biomarker options to visualize and treat proinflammatory leukocytes. There are 3 crucial factors in the design and application of inflammation-targeted radiotracers for cardioimmunology: selective binding to some population of inflammatory leukocytes easily distinguished from the background; the capacity to increase tracer signal to predict functional outcome independently of infarct size; and an imaging signal sensitive to treatments lowering inflammatory cell activity or infiltration of the damaged region. Ideally, new imaging agents should undergo robust characterization of binding characteristics in healthy and diseased myocardium and in response to known efficacious therapy. Although 18F-FDG as described above displays some selectivity for a range of activated leukocytes, the ability to resolve inflammation from variable metabolism in the surviving myocardium hinders its reliability as a prognostic or theranostic marker. Accordingly, several alternative imaging approaches have been developed.
Alternative Targets and Tracers for Inflammation Imaging in Cardiovascular Disease
Overview of cellular targets for novel inflammation radiotracers. Shown are literature-based promiscuity and selectivity of inflammation-targeted radiotracers for distinct leukocyte components of inflammatory process. Myeloid and lymphoid cell types are pictured, including neutrophils, proinflammatory and reparative monocytes and macrophages, B lymphocytes, and T lymphocytes. Imaging targets exhibit range of selectivity for these cell populations based on literature, including in vitro uptake assays and in vivo imaging with ex vivo validation. CD206 = mannose receptor; GLUT = glucose transporter; ICOS = inducible T-cell costimulator; LAT = L-type amino acid transporter; SSTR = somatostatin receptor.
Methionine
In the infarct territory of mice after coronary artery occlusion, there was an increased 11C-methionine accumulation paralleled by increases in CD11b-positive cells in the left ventricle (30). Uptake by cardiomyocytes in vivo was negligible, providing lower background signal than 18F-FDG at isolating the inflammatory signal. Treatment with an antibody cocktail to inhibit integrin-mediated leukocyte infiltration lowered the localized 11C-methionine signal (30). In a rat model of autoimmune myocarditis, uptake of 11C-methionine was elevated in myocardial regions with an elevated CD68 macrophage density and correlated strongly with 18F-FDG uptake (31). Clinical experience with 11C-methionine in cardiovascular disease is limited, but initial data suggest that 11C-methionine is enriched in the reperfused infarct within 1 wk of the onset of symptoms and declines at 3 and 6 mo after successful reperfusion and therapy (32).
Chemokine CXC Motif Type 4 Receptor (CXCR4)
Translational studies using 68Ga-pentixafor, a pentapeptide targeting CXCR4, established that there is a transient increase in tracer signal in the infarct region and border zone after coronary occlusion in mice and in the first days after the first ST-elevation myocardial infarction in patients (33). Despite a lower affinity of 68Ga-pentixafor for the mouse variant than for the human variant of CXCR4, the infarct territory signal was effectively blocked by the CXCR4 inhibitor AMD3100 (33). The elevated infarct region signal was similar between permanent occlusion and reperfused myocardial infarction in mice and correlated inversely with left ventricle ejection fraction 6 wk after coronary occlusion, independently of the infarct size (34). Moreover, in the first week after myocardial infarction, mice that died of left ventricle rupture, a rare clinical event but involving mechanisms similar to those of infarct expansion in humans, had a significantly higher CXCR4 signal at 3 d after injury, reflecting delayed resolution of inflammation (34). Treatment to reduce splenic myeloid cell mobilization using moderate-dose angiotensin-converting enzyme inhibitors lowered the accumulation of 68Ga-pentixafor in the infarct territory, and this lowering corresponded to improved functional outcome (33,34). In pressure-overload heart failure induced by transverse aortic constriction in mice, the CXCR4 PET signal was persistently elevated in the global myocardium over 6 wk compared with sham-operated animals (35). Higher 68Ga-pentixafor uptake at 1 wk correlated with a larger change in ventricle volume, reflecting predictive value for adverse remodeling in heart failure (35). Initial clinical studies identified a variable CXCR4 signal in patients after acute myocardial infarction (34,36). Tracer uptake was localized to segments that exhibited both late gadolinium enhancement and edema on T2-weighted cardiac MRI (33), reflecting acute infarcted myocardium rather than a scar or border zone. Moreover, a higher infarct region 68Ga-pentixafor signal in the first days after infarction predicted a lower functional outcome and higher incidence of major adverse cardiac events (Fig. 3) (34,36). In addition to hard events, the CXCR4 imaging signal identified an elevated risk in the early stages of the disease, with a direct correlation between infarct region 68Ga-pentixafor uptake and ejection fraction on short-term follow-up (34).
Clinical imaging of CXCR4 after acute myocardial infarction in patients. Two patients exhibit divergent uptake of 68Ga-pentixafor in region of perfusion defect. (Lower left) High range of signal intensity (infarct-to-remote activity ratio) is seen among patients. Major adverse cardiac events are defined as hard (cardiac death, nonfatal myocardial infarction, nonfatal stroke; green symbols) or soft (unplanned revascularization, rehospitalization for heart failure; green symbols). Red and black squares represents case examples at upper left and right, respectively. (Lower middle) 68Ga-pentixafor IRR correlated with infarct size defined by perfusion defect. (Lower right) IRR above 1.85 predicted higher incidence of major adverse cardiac events. HLA = horizontal long axis; IRR = infarct-to-remote activity ratio; MACE = major adverse cardiac events; MIBI = methoxyisobutylisonitrile; SA = short axis; VLA = vertical long axis. (Reprinted with permission of (36).)
Chemokine CC Motif Type 2 Receptor (CCR2)
CCR2 is a more specific marker of bone marrow–derived monocytes and macrophages involved in the early stages of proinflammatory activity. CCR2 can be imaged using radiolabeled DOTA-extracellular loop 1 inverso (ECL1i). Elevated CCR2 expression is observed in circulating monocytes associated with arterial wall inflammation. In mice after coronary artery occlusion, 68Ga-DOTA-ECL1i uptake at the site of injury was increased transiently, with a maximal signal at 4 d. The intensity of the imaging signal correlated directly with expression of CCR2-positive monocytes in the left ventricle and correlated inversely with contractile function at 4 wk (Fig. 4) (37). Elevated CCR2 expression was further identified in human heart specimens from acute myocardial infarction and in chronic ischemic cardiomyopathy hearts, demonstrating an increased signal that could be blocked by an excess of unlabeled compound. Moreover, tracer uptake directly correlated with the presence of CCR2-positive macrophages but not CCR2-negative macrophages on immunostaining (37), supporting the higher selectivity for inflammatory monocyte recruitment and macrophage accumulation. In a model of heart transplantation, 64Cu-DOTA-ECL1i identified localized CCR2-positive cell accumulation in the donor heart (38), proportional to flow cytometry. These studies investigated the feasibility of isolating a specific cell subpopulation in the inflammatory process—a method that may be more amenable to therapeutic modulation than are broad antiinflammatory approaches.
Preclinical imaging of CCR2 after acute myocardial infarction in mice. Increased 68Ga-DOTA-ECL1i uptake (upper right) is seen in nonviable infarct region (indicated by arrows) after coronary artery occlusion defined by 18F-FDG imaging in the same mouse (upper left). Uptake corresponded to higher cardiac density of CCR2-positive and major histocompatibility complex II–negative infiltrating monocytes identified in lower right quadrant of flow cytometry charts (lower left). Intensity of 68Ga-ECL1i uptake as percentage injected dose per gram of tissue at 4 d after injury inversely correlated with contractile function at 4 wk (lower right). %ID = percentage injected dose; MHC-II = major histocompatibility complex II; MI = myocardial infarction; MIP = maximum-intensity projection. (Reprinted with permission of (37).)
TSPO Ligands
The mitochondrial 18-kDa translocator protein (TSPO) is highly expressed by activated microglia in the central nervous system and is the target of multiple generations of radioligands to image neuroinflammation. TSPO is also expressed by peripheral macrophages, providing an additional and available imaging biomarker of inflammation for cardiovascular disease. Elevated uptake of 18F-PBR111 was identified in the vessel wall of atherosclerotic plaques in ApoE−/− mice, colocalized to CD11b-positive infiltrative macrophages (39). In mice after acute myocardial infarction, a transient increase in TSPO ligand binding is observed within the first week after coronary artery ligation, corresponding to elevated levels of CD68 macrophages in the infarct territory and border zone (40,41). The intensity of the early TSPO signal predicts the subsequent ejection fraction independently of the infarct size (41). Depletion of macrophages before coronary artery ligation ablates the TSPO imaging signal in the infarct territory (42). Treatment with the angiotensin-converting enzyme inhibitor enalapril lowers the cardiac TSPO PET signal early after experimental myocardial infarction, in parallel with a decreased CD68-positive macrophage content in the left ventricle and improved contractile function at 8 wk after injury (43). Isolation of the inflammatory signal is complicated by the nonzero uptake of TSPO ligands in healthy and remote noninfarcted myocardium, though this complication may be addressed by kinetic modeling (40). In fact, the TSPO expression and PET signal tend to be elevated in the noninfarcted myocardium of mice with heart failure, reflecting mitochondrial stress in late-stage cardiovascular disease (41,44). Patients after myocardial infarction also exhibit a higher TSPO signal within the perfusion defect territory (41), but clinical experience is limited by, in part, the background activity in noninfarcted myocardium.
Somatostatin Receptor
Somatostatin receptor 2 is expressed by activated inflammatory macrophages, with increased upregulation of expression compared with glucose transporters (45). In mice, 64Cu-DOTATATE SUVmax was reported to be elevated in the infarct region at 3 d after coronary artery ligation (46). Conversely, another study found that 68Ga-DOTATATE mean uptake did not differ from sham-operated mice 3 d after infarction (47). In both studies, visual delineation of the infarct territory was poor, reflecting rapid clearance of the tracer from the bloodstream. By contrast, patients with large-vessel vasculitis exhibit robust uptake of somatostatin receptor ligands in the vessel wall as measured by SUVmean and target-to-background ratios (48). Effective treatment with methotrexate resulted in marked reduction in the somatostatin receptor PET signal after a median of 9 mo (Fig. 5) (48). Patients with acute myocardial infarction display localized uptake of 68Ga-DOTATOC in segments corresponding to T2-weighted MRI edema and mild uptake in regions with a late gadolinium enhancement scar (49). Diffuse tracer uptake was also observed in patients with active peri- or myocarditis (49). As with other inflammation imaging agents, dedicated prospective clinical trials are warranted to decipher the added value of imaging in patient management.
Clinical imaging of somatostatin receptor in large-vessel vasculitis. (A) Repeated imaging in patients with large-vessel vasculitis shows that robust uptake (arrows) of 18F-FDG (left panel) and 18F-FET-βAR-TOCA (center panel) is present in affective vessel wall initially but absent after 15 mo of steroid and methotrexate therapy (right panel). (B) By contrast, untreated vasculitis shows persistent signal in vessel wall. GCA = giant cell arteritis; FET-βAG-TOCA = 18F-fluoroethyltriazole-βAG-TOCA. (Reprinted with permission of (48).)
Mannose Receptor
Selective imaging of reparative myeloid cells has been proposed to detect the resolution of adverse inflammation after injury. Several cell surface markers are specifically expressed by reparative macrophage subpopulations, with the most extensively characterized for imaging being the mannose receptor CD206. A single study using 18F-deoxymannose reported noninferior uptake compared with 18F-FDG in atherosclerotic plaques in a rabbit model (50) but did not definitively identify distinct lesions from the conventional imaging approach. In myocardial infarction, imaging of mannose receptor using 68Ga-labeled single-domain antibody identified a delayed increase in the imaging signal relative to other imaging agents targeting proinflammatory macrophage subtypes, with a maximal signal being reached at 7 d after coronary ligation in mice (51). Autoradiography demonstrated localized uptake within the border zone. The propensity of diverse macrophage subtypes in chronic heart failure may be attractive, but no studies have yet been reported in the literature. Although antiinflammatory therapy is associated with increased mannose receptor content in the heart after, for example, myocardial infarction, the sensitivity of mannose receptor imaging agents to these changes requires validation to demonstrate the value of reparative macrophage imaging in therapeutic management.
Lymphocyte-Imaging Agents
For the adaptive immune system, fewer agents have seen application in cardiovascular disease. Although some of the imaging agents listed above exhibit some crossover to lymphocytes, the arsenal of radiotracers targeting these cells is comparatively limited. However, new imaging agents targeting T cells have begun to emerge in oncology (52). Monitoring of T-cell activation in response to allogenic transplantation has been demonstrated using 2′-deoxy-2′-18F-fluoro-9-β-d-arabinofuranosylguanine in secondary lymphoid organs after hematopoietic cell transplantation in mice (53). Immuno-PET imaging has seen broader application in predicting response to immune checkpoint inhibitor therapy, in which noninvasive measurement of T-cell elements is valuable. Radiolabeled single-domain antibodies against T-cell elements, including CD4, CD8, or inducible T-cell costimulator, detect activated T cells (54–56) and may provide disease-progression insights that may subsequently be applied in the heart.
THE FUTURE
Role of Radionuclide Imaging in Cardioimmunology and Therapy
The parallel evolution of targeted antiinflammatory therapy and selective immune cell–imaging agents provides a pathway toward personalized therapy in cardiovascular disease. Because the extent and intensity of the inflammatory response after injury are individually varied, patients are unlikely to respond equally to the same therapy. How can patient risk be stratified more effectively? Can we identify those patients most likely to benefit from targeted and costly antiinflammatory therapy? This concept builds outward from experience in oncology, for which imaging biomarkers can provide both diagnostic and therapeutic value. That is, molecular imaging can identify the presence or absence of the therapeutic target before the treatment begins, and repeated imaging can measure the efficacy of the treatment to ensure patient response and provide an indication of molecular efficacy that will benefit drug development (Fig. 6). This expanded definition of theranostics, coupling the imaging agent to the therapy through the inflammatory response at a specific locus, cell type or subtype, or marker, bears potential to revolutionize the application of molecular imaging in cardiovascular disease.
Theranostic paradigm for cardioimmunology. Targeted molecular imaging agent is used to screen patients with cardiovascular disease for intensity of inflammation as predictor of subsequent ventricular remodeling. Those with high imaging signal are selected for specific molecular antiinflammatory treatment on basis of imaging timeline. Patients without this image signature are given alternative treatment because they are unlikely to respond to selective therapeutic. MIP = maximum-intensity projection.
Imaging-Guided Therapy
Although complete clinical studies are lacking, the platform for imaging-based therapeutic guidance has been established in preclinical studies evaluating the prognostic value of inflammation imaging. Proinflammatory leukocyte markers, including glucose metabolism, CXCR4, CCR2, somatostatin receptor, and TSPO, have all demonstrated the predictive value of the early imaging signal for subsequent functional outcome (23,34,37,41,48). Taking this concept forward, the imaging time course can identify the optimal timing of therapy to support endogenous inflammatory resolution and repair. The most complete assessment of this idea has been reported for CXCR4 imaging with 68Ga-pentixafor.
Inhibition of CXCR4 reduces mobilization of monocytes and derivative macrophages to the damaged region after myocardial infarction, but the timing of this intervention drastically impacts the efficacy of the treatment. Whereas continuous inhibition of CXCR4 in mice results in infarct expansion and reduced capillary density, a single dose improves contractile function and results in smaller infarct sizes (57,58). Given the imaging timeline of CXCR4, in which the CXCR4 signal 3 d after infarction independently predicted worse outcome among surviving mice, single-time treatment at the time of the elevated signal (3 d) resulted in improved functional outcome compared with single-time treatment at a time when the PET signal had returned to baseline levels (7 d) (34). Specifically, the imaging-guided timed intervention lowered the total number of infiltrating myeloid cells to the infarct and border zone and saw a preferential shift in the proportion of reparative leukocyte subpopulations over proinflammatory monocytes and neutrophils (34). As such, imaging-based guidance bears potential to optimize therapeutic timing.
Challenges and Opportunities
Adoption of this theranostic paradigm requires several critical studies. First, it is essential that we understand the cellular basis of the imaging signal, irrespective of the imaging target. Detailed comparison of regional tracer uptake with large-scale -omics datasets will be invaluable in both deciphering high-potential imaging agents and discriminating novel therapeutic targets. Second, in vivo imaging signals must provide robust and reproducible quantitative values that can be compared reliably across multiple centers and disease models. Accordingly, tracer availability at multiple sites will be important to establish a broader footprint for the methodology. Third, the value of the imaging signal must also be demonstrated regarding independent predictive value (beyond the infarct size alone) and ability to resolve response to targeted therapy, as a key component of the theranostic concept. This requires thorough preclinical studies and prospective clinical trials that establish the basal binding signal in healthy tissue and determine the optimal time point for effective imaging relative to long-term outcome. Such trials are beginning to emerge, with a focus on imaging in the heart and in myeloid and lymphoid organs (NCT05519735). Finally, the added value of imaging-guided therapy will need to be established clinically and for multiple high-potential inflammation imaging agents. This may be investigated through different local targeting methods (e.g., targeted lipid nanoparticles), patient-by-patient selection based on the imaging signal, or precisely timed intervention based on the inflammatory signal time course. Although these are formidable challenges, such experiments can realize theranostic applications in cardiovascular imaging and build toward an exciting future in which imaging plays an important role in the management of individualized treatment of cardiovascular disease.
CONCLUSION
The development of cardioimmunology as a field presents an opportunity for a tangible connection between cardiovascular molecular imaging and personalized therapy. The expanded arsenal of imaging agents targeting specific components of the inflammatory cascade parallels refined therapeutic approaches that seek to isolate adversarial from beneficial immune cell activity. Noninvasive monitoring of not only the progression of disease but also the regression in response to therapy can revolutionize how imaging is used in cardiac patient management. Just as imaging can guide therapy, the experience of past and present immune cell imaging enables navigation of the path from image to individualized medicine, propelling cardiovascular molecular imaging into the future.
DISCLOSURE
This work was partly supported by grants from the Leducq Foundation (20CVD02) and the German Research Foundation Heisenberg Program (TH 2161/3-1, James Thackeray). No other potential conflict of interest relevant to this article was reported.
Footnotes
Published online Nov. 1, 2023.
- © 2023 by the Society of Nuclear Medicine and Molecular Imaging.
REFERENCES
- Received for publication July 30, 2023.
- Revision received September 12, 2023.
In this issue
Jump to section
Related Articles
Cited By...
- No citing articles found.