Research ArticleBasic Science Investigation

Myocardial Fibrosis: Emerging Target for Cardiac Molecular Imaging and Opportunity for Image-Guided Therapy

Frank M. Bengel, Johanna Diekmann, Annika Hess and Michael Jerosch-Herold
Journal of Nuclear Medicine November 2023, 64 (Supplement 2) 49S-58S; DOI: https://doi.org/10.2967/jnumed.122.264867

Abstract

Myocardial fibrosis is a major contributor to the development and progression of heart failure. Significant progress in the understanding of its pathobiology has led to the introduction and preclinical testing of multiple highly specific antifibrotic therapies. Because the mechanisms of fibrosis are highly dynamic, and because the involved cell populations are heterogeneous and plastic, there is increasing emphasis that any therapy directed specifically against myocardial fibrosis will require personalization and guidance by equally specific diagnostic testing for successful clinical translation. Noninvasive imaging techniques have undergone significant progress and provide increasingly specific information about the quantity, quality, and activity of myocardial fibrosis. Cardiac MRI can precisely map the extracellular space of the myocardium, whereas nuclear imaging characterizes activated fibroblasts and immune cells as the cellular components contributing to fibrosis. Existing techniques may be used in complementarity to provide the imaging biomarkers needed for the success of novel targeted therapies. This review provides a road map on how progress in basic fibrosis research, antifibrotic drug development, and high-end noninvasive imaging may come together to facilitate the success of fibrosis-directed cardiovascular medicine.

Fibrosis is a key mechanism in adverse cardiac remodeling and in the development and progression of heart failure. In various cardiac pathologies, the presence, extent, and activity of fibrosis contribute to contractile dysfunction and arrhythmia and thereby to adverse outcomes. Accordingly, there is sustained interest in the development of antifibrotic therapies that seek to prevent, stop, or even reduce fibrotic activity (1,2). Some established drugs, such as angiotensin-converting enzyme inhibitors or mineralocorticoid receptor antagonists, are known to have beneficial antifibrotic effects that accompany their main target effects. But specific and highly effective therapeutic approaches for cardiac fibrosis are still lacking (1). On the basis of the recent success of molecule-targeted drug development and an improved understanding of profibrotic mechanisms, a range of novel antifibrotic agents, including small molecules and RNA- or cell-based therapeutics, is under development (3–5). These novel, highly specific treatments will require guidance by equally specific diagnostic algorithms for precise identification of the most suitable candidates (3). Because fibrosis is a complex and dynamic process of tissue transformation that includes a heterogeneous spectrum of effector cells, various signaling pathways, and the tightly organized molecular network of the extracellular matrix (ECM) (6), it is unlikely that a single biomarker will suffice for this purpose. Myocardial biopsy is not a routine procedure and is hampered by sampling error, limiting the feasibility of histologic tissue biomarkers for therapy guidance. Circulating biomarkers may give insight into ECM production or degradation, but those are not necessarily representative of fibrosis in the heart and may be affected by the state of other organs that undergo changes in heart failure, too (7). Accordingly, noninvasive imaging holds promise to provide imaging biomarkers that specifically define the individual state of myocardial fibrosis (8). Indeed, various novel imaging methodologies have emerged that allow for an increasingly precise, noninvasive characterization of myocardial tissue biology.

This review highlights how improved mechanistic insights, novel specific treatments, and continued progress in noninvasive imaging will converge toward a future of image-guided, molecule-targeted antifibrotic therapy in cardiovascular medicine.

MYOCARDIAL FIBROSIS: PATHOPHYSIOLOGIC CONSIDERATIONS

In very general terms, fibrosis may be defined as an accumulation of excess ECM components in injured tissue and is a common pathologic hallmark of many disease entities (6). On a broad level, fibrosis can be further subdivided into reparative or replacement fibrosis and reactive fibrosis, the latter including both interstitial and perivascular fibrosis (Fig. 1) (1). In the heart, replacement fibrosis is needed to stabilize areas of major tissue injury, for example, by scar formation after acute myocardial infarction (AMI). In contrast, reactive fibrosis is a more subtle response to a variety of chronic triggers that contribute to the development and progression of heart failure. Such triggers include mechanical stretch and inflammation, pressure overload, various cardiomyopathies, and even the process of aging (1). Different types of fibrosis may coexist, depending on the individual pathology. AMI, for example, will result in a replacement scar but may trigger interstitial and perivascular fibrosis in remote myocardium, where the fibrosis contributes to adverse remodeling (3). And pressure overload, for example, may initially induce perivascular fibrosis through microvascular disease but may also induce interstitial fibrosis due to altered mechanical conditions, as well as replacement fibrosis in cases of substantial cellular loss and tissue injury (9,10). Additionally, fibrosis not only may be heterogeneous on an intra- and interindividual level but also is characterized by temporal dynamics, which will depend on the timing of trigger signals and on the activity of a variety of cellular, subcellular, and molecular profibrotic mechanisms. Importantly, both the extracellular and the cellular components of fibrosis contribute to its dynamic nature. For an in-depth review of the pathobiology of fibrosis and its molecular mechanisms, the reader is referred to dedicated review articles (1,2,5,6,11). A brief summary of mechanisms relevant for novel imaging methods and for therapies that may be guided by imaging is given in the following and summarized in Table 1.

FIGURE 1.
FIGURE 1.

Histologic patterns of myocardial fibrosis. Shown are Masson trichrome stains of mouse heart 3 wk after ischemia–reperfusion injury. Fibrotic areas are stained in blue; viable tissue, in red. Top shows short-axis overview of entire left ventricle. Bottom shows magnifications of representative areas of replacement fibrosis in infarct scar region and interstitial and perivascular fibrosis in remote myocardium. Note that all 3 qualities of tissue fibrosis coexist in same heart.

View this table:
TABLE 1.

Key Features of Myocardial Fibrosis

Fibrogenic activity leads to excess ECM, which consists of a network of extracellular macromolecules, including large proteins such as collagens and elastins, proteoglycans, and hyaluronic acid. Adhesion molecules, such as fibronectin, laminin, or integrins, establish the connection between ECM and associated cells. Accumulation of ECM, however, is not a terminal and irreversible state (6). Relief from chronic pressure overload or elimination of profibrotic activated fibroblasts will, for example, resolve preexisting interstitial myocardial fibrosis (12,13). ECM is dynamically organized by an array of enzymes and signaling molecules, which modulate not only matrix formation and maturation but also its degradation. Some ECM molecules, enzymes, or cleavage products may be released into the bloodstream and serve as systemic markers of collagen production (e.g., procollagen type I or type III N-terminal propeptide) or degradation (e.g., matrix metalloproteinases or their tissue inhibitors) (1).

Besides ECM, the cellular substrate for fibrosis has been increasingly moving to the foreground of research in the field (5,6,11). At its center is the fibroblast, which gets activated by profibrotic triggers, differentiates to a myofibroblast, and actively produces ECM (5). In pathologic conditions, fibroblasts are a heterogeneous population of cells. A recent multiomics analysis, for example, confirmed the presence of a range of fibroblast subpopulations after myocardial infarction (14). A subcluster that was most actively expressing ECM was specifically marked by the periostin, collagen 1A1, and fibronectin 1 genes; overexpressed the transcription factor RUNX1 that promotes myofibroblast differentiation; and was enriched in ischemic tissue (14). More recently, single-cell analysis further characterized a profibrotic fibroblast subpopulation with a similar profile (i.e., high expression of collagen, periostin, and RUNX1) as being associated with the surface marker fibroblast activation protein (FAP) (15). This is consistent with prior immunohistologic work (16) and supports FAP as a marker of matrix-producing activated fibroblasts.

In addition to a continuously increasing depth of single-cell–based information about fibroblast heterogeneity, the tight interaction between fibroblasts and the immune system, along with its impact on the regulation of profibrotic activity, has been another focus of concurrent research. Tissue injury triggers an immediate immune response, which clears cellular debris and organizes repair but may also contribute to remodeling and heart failure development (3,4). Signaling between innate and adaptive immune cells and fibroblasts is critical in this process (3,5,11). Consistently, spatial multiomics mapping confirmed the association and interaction between macrophage and fibroblast states after myocardial injury (14), and very recent work suggested that a subset of macrophages, characterized by C-C chemokine receptor type 2, triggers a profibrotic fibroblast phenotype via interleukin 1 β-signaling (15). In addition, the very prominent profibrotic and fibroblast-activating effects of transforming growth factor β, which is produced by a broad range of leukocytes, has been known for decades and is considered a key regulator of fibrosis in many organs (17), including the heart (5). Aside from transforming growth factor β, a variety of other signaling molecules has been identified to contribute to the crosstalk between the immune system and fibroblasts in activation, persistence, and resolution of profibrotic phenotypes (11).

When taken together, the broad range of individual triggers, the various tissue patterns, the diverse composition and turnover of the ECM, the spectrum and heterogeneity of involved cell populations, and the activity and interplay of molecular signaling mechanisms all strongly support the notion that the phenotype of myocardial fibrosis may be very heterogeneous (1). Additionally, it remains challenging to distinguish the reparative fibrotic response associated with physiologic healing from the dysregulated, adverse state of persistent, reactive profibrotic activity that contributes to the progression of heart failure. This has implications for the development and selection of novel, appropriate antifibrotic therapeutics, as well as for diagnostic biomarkers that will be needed to enable precision interventions.

EMERGING ROLE OF MYOCARDIAL FIBROSIS AS A THERAPEUTIC TARGET

The development of specific antifibrotic therapies has been a major research focus in cardiovascular medicine for several years (1,2,5,9). Improved understanding of the mechanisms of fibrosis led to identification of key mechanisms and pathways leading to ECM buildup that may be targeted by potential therapies (11). However, scientific progress has also provided increasing evidence that fibrosis is a highly dynamic process with inherent plasticity that needs to be considered for the design of therapeutic interventions (6). To date, the accessory antifibrotic effects of some heart failure drugs such as angiotensin-converting enzyme inhibitors have been identified and are considered to contribute to their cardioprotective effects (5). Specific drugs with primary antifibrotic effects are not yet clinically available in cardiovascular medicine (1), and such agents are generally few in the field of molecular medicine (6). But continued progress in mechanistic research, including single-cell multiomics analysis, is leading to an increasing spectrum of targeted antifibrotic agents that are crossing the bridge from preclinical testing toward clinical trials (18). Various strategies may be pursued for treatment of cardiac fibrosis, and some examples are highlighted in Table 2. Although a detailed discussion is available elsewhere (1,6,9) and is considered beyond the scope of this article, 3 common trends should be noted.

View this table:
TABLE 2.

Various Strategies for Treatment of Myocardial Fibrosis

First, as opposed to the ECM and its composition, which is a product of cellular activity, the cells that are involved in fibrosis are emerging as a primary focus of both mechanistic analyses and intervention design. Mechanisms of fibroblast activation and immune cell–fibroblast crosstalk are promising examples for a potential exploitation by targeted drug development (4,5,11). Second, the increasing data supporting the dynamics of fibrosis and the plasticity of fibroblasts are leading to efforts to exploit this plasticity for therapeutic purposes by adopting strategies that go beyond a single drug target. The recent development of epigenetic interventions using, for example, micro-RNA or long noncoding RNA (19) and the introduction of chimeric antigen receptor T-cell–based approaches for reversing cardiac fibrosis (12,20) are important examples for novel therapies that seek to modulate entire systems of mechanisms rather than the single molecular targets that are often addressed by proteins or small molecules. And third, given the complexity and dynamics of the pathobiology of fibrosis, it is increasingly perceived that novel, sophisticated antifibrotic interventions will not work in every patient with every underlying disease every time (1,3,6). The need for personalization and diagnostic guidance by biomarkers is well recognized but remains an unresolved need and, thus, an opportunity for modern noninvasive imaging.

NONINVASIVE IMAGING BIOMARKERS OF MYOCARDIAL FIBROSIS

Noninvasive imaging modalities provide a range of techniques to characterize myocardial fibrosis. The currently available methods for clinical application are summarized in Table 3.

View this table:
TABLE 3.

Imaging Techniques for Characterization of Myocardial Fibrosis

Echocardiography

Echocardiography is a ubiquitous, fast, and safe imaging method for the assessment of myocardial structure and function. In the routine clinical setting, echocardiography typically describes left ventricular (LV) remodeling, which is characterized by impaired LV ejection fraction and by increased LV volumes and mass. Impaired LV ejection fraction determined by echocardiography is a strong indicator of adverse outcome but lacks the specificity to characterize myocardial damage along with the severity and activity of fibrosis in more depth (21,22). More recently, advanced methods such as strain imaging have been implemented to identify further aspects of functional impairment. Detectable strain vectors (longitudinal, circumferential, and radial) result from obliquely and oppositely orientated subendocardial and epicardial myofibers. Typically, torsional ventricular contraction is generated through an apical counterclockwise twist and a basal clockwise twist (23,24). LV global longitudinal strain from speckle-tracking echocardiography identifies myocardial deformation. It is the most widely used strain parameter. Although the results of echocardiography depend on the reader’s experience, strain acquisitions have been shown to be reliable (25), and guidelines for standardized imaging have recently been established (26). An additive diagnostic and prognostic value for LV global longitudinal strain has been confirmed for various diseases associated with myocardial fibrosis. A metaanalysis of 5,721 individuals with diverse cardiac diseases concluded that LV global longitudinal strain was a stronger predictor of all-cause mortality and a composite of cardiac death, heart failure hospitalization, and malignant arrhythmias than was LV ejection fraction (27). LV global longitudinal strain was also reported to be a predictor of mortality, independent of LV ejection fraction, in patients with heart failure with reduced ejection fraction (27,28). Benefits of strain imaging have also been shown in patients with AMI (29), aortic stenosis (30), mitral or aortic regurgitation (21), and LV hypertrophy (22). Furthermore, strain imaging has been proposed as the test of choice in guidelines for monitoring of asymptomatic cardiotoxicity related to chemotherapy (31). But despite the clear-cut diagnostic value of functional measures and strain imaging from echocardiography, they assess the consequences of fibrosis and do not allow for direct identification and quantification of the type, extent, or activity of myocardial fibrosis.

Cardiac MRI (CMR)

The MR signal from hydrogen nuclei is sensitive to the molecular environment, which can manifest itself through the relaxation times T1 (32) and T2* (33,34), magnetization transfer and chemical exchange effects (35), changes in tissue water diffusion characteristics (36), and myocardial stiffness measured by MR elastography (37). Compared with nuclear imaging techniques, MRI has relatively low sensitivity; therefore, molecular tracers with particular affinities, such as to collagen and fibroblasts, have been developed primarily for nuclear imaging and much less so for CMR, although there has been some success with molecule-targeted CMR in the preclinical setting (38,39). Notwithstanding these limitations, MRI offers several strengths such as potential from endogenous contrast mechanisms that are sensitive to fibrosis and the ability to combine myocardial fibrosis detection with high-resolution imaging of cardiac anatomy and function.

Replacement fibrosis in the form of scar tissue after myocardial infarction can be detected by extracellular gadolinium-based contrast agents. The late gadolinium enhancement (LGE) within 5–10 min after administration results from an expanded extracellular volume. LGE imaging is designed to maximize the contrast between focal fibrosis or infarcted tissue and normal myocardium. Diffuse interstitial fibrosis, which may affect the entire heart, cannot be well characterized by LGE. The buildup of interstitial fibrosis leads to an expansion of ECM, which increases extracellular volume so that it can be estimated by T1 mapping before and after administration of gadolinium-based contrast agents. The change in relaxation rates in myocardial tissue resulting from contrast injection, normalized by the change in relaxation rates in blood and corrected by the hematocrit, provides the myocardial extracellular volume fraction (ECV). ECV quantification is a well-established and histologically validated (40) approach to assessing the burden from diffuse myocardial fibrosis in a range of cardiac diseases (41). In contrast to T1, ECV is independent of magnetic field strength. The use of ECV as a biomarker has been sufficiently successful to spur the development of contrast-based CT imaging protocols for its quantification using the change in Hounsfield unit attenuation before and after contrast administration (42).

The native myocardial T1 relaxation time in the absence of contrast enhancement also changes with expansion of the extracellular volume and for this reason has been used as a myocardial fibrosis imaging biomarker, with the advantage that it does not require injection of a potentially nephrotoxic contrast agent. The sensitivity of native T1 to expansion of extracellular volume is based on the difference in intrinsic relaxation rates between the intracellular and interstitial spaces (43), a difference that is relatively small (∼0.3 s−1). Accordingly, changes in ECV have relatively small effects on native T1, and extracellular contrast can result in much larger effects to quantify ECV (Fig. 2). This may be one reason why some studies report significant changes in ECV but no significant effects for native T1. Of note, factors other than ECV expansion can affect native T1, such as fatty infiltration and amyloid deposition, and these can confound the interpretation of native T1.

FIGURE 2.
FIGURE 2.

Characterization of ECM by CMR. (A) With buildup of interstitial fibrosis, extracellular volume expands, and its quantification as ECV provides surrogate marker of interstitial fibrosis. Intracellular T1 is shorter than interstitial T1, and increase in ECV results in increase in native T1. (B) CMR T1 mapping is used to measure myocardial T1 both without (native T1) and with contrast agent. With simultaneous quantification of T1 of blood (e.g., in LV cavity), one can estimate ECV. Change in myocardial R1 relaxation rate (R1 = 1/T1) per unit change of R1 in blood, which corresponds to slope of dashed lines multiplied by (1 − hematocrit/100), with hematocrit expressed as percentage, provides estimate of ECV. Both lower native R1 and higher postcontrast R1 in myocardial tissue with expanded extracellular volume contribute to higher ECV estimate from T1 mapping.

ECV has also been used to estimate the total cardiomyocyte mass, which is bound to decrease with replacement fibrosis. The LV cardiomyocyte mass index is estimated from (1 − ECV) multiplied by the LV mass index. Whether a decrease in cardiomyocyte mass is due to changes in cardiomyocyte dimensions or to a decrease in the number of cardiomyocytes, for example, due to apoptosis that frequently accompanies processes leading to myocardial fibrosis, cannot be determined by considering only the cardiomyocyte mass index. Nevertheless, changes in cardiomyocyte dimension can affect ECV, as the latter represents a volume fraction. This means that without a change in fibrotic burden and interstitial volume, ECV will, for example, increase with regression of cardiomyocyte hypertrophy. In patients undergoing aortic valve replacement, ECV was found to increase slightly after 1 y whereas LV hypertrophy regressed (44). For an understanding of remodeling over time, it is therefore important to assess both cellular and extracellular components of tissue composition. Interestingly, changes in cardiomyocyte diameter may be quantified by expanding the theory underlying ECV to consider the effects of water exchange between extra- and intracellular spaces. The rate of water exchange is a measure of the intracellular lifetime of water, which can be determined by CMR and increases with cardiomyocyte diameter (45). It has been shown that the buildup of myocardial fibrosis resulting from treatment with potentially cardiotoxic agents, such as anthracyclines in women treated for breast cancer, is accompanied by a reduction in intracellular water lifetime as a histologically validated surrogate for cardiomyocyte diameter (45). This means not only that anthracyclines may lead to interstitial fibrosis but also that their effects, reflected by an increase in ECV, encompass a change in cardiomyocyte diameter or cross-sectional area associated with anthracycline-induced atrophy and apoptosis (46).

Finally, there is a quest for more specific imaging biomarkers of fibrosis that do not require an exogenous contrast agent: one approach takes advantage of the very short T2* relaxation times of hydrogen nuclei in connective or fibrotic tissue and the water surface layers, compared with the signal from bulk water. This requires imaging sequences with ultrashort echo times (33). Additionally, magnetization transfer techniques aim at assessing macromolecular changes associated with some types of myocardial fibrosis (47). It remains unclear whether these non–contrast-based approaches that detect hydrogen nuclei tied to connective tissue render it feasible to quantify diffuse interstitial fibrosis. Furthermore, these biomarkers not only may reflect changes in connective tissue content but also are presumably affected by necrosis and the associated loss of mitochondrial protein content or an increase in water mobility within myocardial scar tissue (47). Combining different endogenous contrast mechanisms and weightings may nevertheless allow for identifying a fingerprint for myocardial fibrosis.

CMR offers a still-evolving array of methods to characterize diffuse and focal myocardial fibrosis. Approaches based on endogenous contrast mechanisms have the potential to fill the role of fibrosis-targeted contrast agents, but endogenous contrast mechanisms generally entail a lower sensitivity and can be confounded by tissue changes other than fibrosis. ECV, as a contrast-based alternative biomarker, provides a robust approach to detecting expansion of the ECM, but this expansion is not exclusive to fibrosis and is also observed in infiltrative cardiomyopathies such as cardiac amyloidosis.

Radionuclide Imaging of FAP

Activated myofibroblasts express the homodimeric membrane-bound serine protease FAP (48–50), which is a marker of profibrotic activity (15) that is not expressed by mature fibrocytes or dormant fibroblasts (16). Accordingly, new FAP-targeting PET radiotracers that were originally developed for oncologic imaging of cancer-associated fibroblasts are now also increasingly used for detection of active fibrotic processes in nononcologic disease (51). FAP-targeted imaging of various cardiac pathologies has become an area of active research, as indicated by a growing number of original articles and case reports (52,53). The hope, supported by preliminary data from these early reports and increasing preclinical evidence, is that specific molecular targeting of FAP provides a new diagnostic tool to identify early changes in fibroblast dynamics and profibrotic activity that are linked to subsequent adverse LV remodeling (54). Once established successfully, such FAP-based imaging markers may identify subjects at elevated risk of heart failure and those who may benefit most from specific therapeutic interventions directed against adverse interstitial myocardial fibrosis.

Early after AMI, FAP expression has been confirmed histologically in the infarct region, and a role in wound healing and remodeling was suggested before FAP tracers were introduced (16). A first-generation tracer, 68Ga-FAPI-04, was used for experimental PET in rats after AMI; a FAP-specific signal peaking 6 d after coronary ligation was reported, with the highest tracer accumulation in the infarct border zone (55). Another FAP-targeted PET tracer, 68Ga-MHLL1, as applied in healthy mice after coronary ligation (56), showed an elevated infarct region signal at 7 d, persisting until 21 d after AMI. These early experimental imaging results support the feasibility of FAP-targeted PET for imaging activated cardiac fibroblasts after AMI. They did not clarify the relative contribution of replacement fibrosis (which is needed for wound healing and tissue repair) versus interstitial fibrosis (which may contribute to dysfunction of otherwise viable myocardium) or, thus, the relationship of the imaging signal and its time course with the development and progression of heart failure. Yet, they provided a foundation for clinical application in patients after AMI. Starting in 2021, there emerged several case reports and pilot studies that consistently confirmed a specific and intense myocardial signal in patients after AMI (57–59). Importantly, in patients after reperfusion, the FAPI tracer signal typically exceeded the hypoperfused infarct region (57), including areas of viable tissue in the border zone, where the injury may contribute to the development of interstitial fibrosis. A typical myocardial tracer distribution is shown in Figure 3. In a comprehensive observational study, 35 AMI patients underwent PET with the second-generation tracer 68Ga-FAPI-46 within 11 d after revascularization for AMI. In a multimodality imaging approach, PET results were compared with global and regional myocardial perfusion assessed by SPECT, as well as with multiparametric CMR and echocardiography, including functional outcome determined at follow-up in a subset of patients (60). A central finding was that the measured myocardial FAP volume was highly variable between individuals despite similar timing after AMI and that the PET signal was predictive of subsequent development of LV dysfunction at follow-up. Another important finding was that PET signal and tissue characterization from CMR (including T1/T2 relaxation times and LGE) did not show complete regional matching. A relevant proportion of segments with specific tracer uptake did not show LGE or prolongation of T1 and T2 relaxation times. This is consistent with the notion that cellular profibrotic activity (as indicated by PET) is not the same as changes in extracellular tissue composition (as indicated by CMR). In fact, information from both modalities, on 2 different aspects of tissue fibrosis, may be complementary. These key findings will need to be confirmed by future larger prospective studies.

FIGURE 3.
FIGURE 3.

Multiparametric imaging of myocardial fibrosis 7 d after acute left anterior descending AMI. (Top row) Representative short-axis slices and LV polar maps of 68Ga-FAPI-46 cardiac PET and myocardial perfusion SPECT. Intense regional FAPI signal is present in anterior and septal myocardial wall, with high contrast to noninfarcted myocardium. Polar map shows fibroblast activation in complete left anterior descending coronary territory and adjacent territories. Perfusion imaging shows significant hypoperfusion in apical to basal anterior myocardial wall. Polar map comparison reveals that area with activated fibroblasts exceeds hypoperfused infarct area and includes border zone. (Bottom row) Representative short-axis CMR images of same patient. LGE and dark area of no reflow is found in anteroseptal wall, consistent with replacement scar. Representative parametric T1, T2, and ECV images show extensive signal elevation exceeding infarct region, consistent with interstitial remote tissue alterations. Sum of images provides information about irreversibly injured infarct region, activation of fibroblasts, and changes in ECM composition in areas of replacement and reactive fibrosis.

Although AMI is a condition that leads to severe activation of profibrotic pathways, this activation is in part needed because irreversibly damaged tissue requires repair. The delicate balance between desired replacement fibrosis in nonviable tissue and adverse activation of interstitial fibrosis in viable tissue makes targeted therapeutic interventions challenging, because they bear the risk of destabilizing the infarct scar formation. Accordingly, other cardiac conditions that may be associated with more subtle but widespread interstitial profibrotic activity are emerging as attractive targets for the introduction of novel antifibrotic molecular therapies. Consistent with this trend, various recent studies have focused on using myocardial FAP imaging in nonischemic cardiomyopathies, systemic diseases, and cardiooncology. The cardiac FAP signal has been evaluated in oncologic patients, and altered myocardial FAP uptake was found, depending on the presence of cardiovascular comorbidities such as arterial hypertension, diabetes mellitus, and obesity (61). Patients with cardiac sarcoidosis (62) and amyloidosis (63) showed intense FAP uptake in affected myocardial areas. And variable but elevated myocardial FAP signal was reported for patients with heart failure (64) and systemic sclerosis (65). Possible cardiooncologic applications of FAPI PET were identified by case reports showing increased myocardial tracer uptake in a patient in checkpoint inhibitor–associated myocarditis (66) and in chemotherapy-induced cardiotoxicity (67). Additionally, pressure overload induced by advanced aortic stenosis has also been associated with various degrees and regional patterns of myocardial FAP signal elevation. Of note, in this setting the FAPI PET regional patterns were again correlated but were not well matched with tissue characterization by CMR and with strain from echocardiography, supporting a complementary role (68). Figure 4 compares patterns of myocardial FAP signal in various cardiac pathologies.

FIGURE 4.
FIGURE 4.

Patterns of myocardial fibroblast activation in patients with various cardiac conditions. Depicted are 68Ga-FAPI-46 cardiac images as representative PET/CT short-axis slice and polar maps of entire left ventricle. (Far left) Patient 1 wk after AMI in left anterior descending coronary artery territory (images identical to Fig. 3). Intense regional FAPI signal elevation can be seen in anterior and septal myocardial wall, with high contrast to noninfarcted myocardium. (Mid left) Patient with pressure overload due to severe aortic stenosis, scheduled for transcatheter aortic valve replacement (TAVR). Heterogeneous, moderately increased myocardial FAPI signal with base-apex gradient and maximum in basal septum can be seen. (Mid right) Patient with idiopathic dilated cardiomyopathy, scheduled for LV assist device implantation. Diffuse, inhomogeneous FAPI signal with elevation can be seen throughout entire LV myocardium. (Far right) Oncologic patient with FAPI signal from infradiaphragmatic hepatic metastases but without known cardiovascular comorbidities. LV tracer signal is not different from blood pool tracer signal.

Radionuclide Imaging of Other Fibrosis-Associated Targets

Although imaging of FAP focuses on the fibroblast and currently enjoys widespread attention because of its success in oncology, a range of tracers has been introduced that target alternative pathways or molecular structures involved in tissue fibrosis. An extensive review of ECM molecular imaging has, for example, been published by De Haas et al. (69), and a review specifically focusing on molecular imaging of cardiac remodeling after AMI has been published by Varasteh et al. (70). Of note, most original work in this area is preclinical, and when compared with FAPI tracers, translation to humans is not as extensive. Some examples are highlighted in the following.

Collagen as the major ECM component has been the target for some SPECT and PET approaches. Using 99mTc-streptavidin–coupled collagelin, specific myocardial tracer uptake was reported in rats after AMI (71). Another SPECT radiotracer, 99mTc-CBP1495, was shown to have a high affinity to collagen type I and showed significantly elevated uptake in fibrotic lung and liver tissue (72). In a first-in-humans study, collagen-targeted 68Ga-CBP8 PET and MRI were performed simultaneously, and elevated tracer signal was detected in fibrotic lung regions versus healthy controls (73). Molecular imaging of matrix metalloproteinases, which are involved in inflammation and reorganization of injured tissue, including ECM deposition and degradation, has been achieved, such as by using 99mTc-RP805 in preclinical SPECT studies (74,75). And the renin angiotensin system may also be interrogated with PET and SPECT. Approaches for the cardiac renin angiotensin system include radiolabeled angiotensin-converting enzyme inhibitors (76) or agents targeting the angiotensin type 1 receptor (77,78), which have been tested in settings of myocardial fibrosis. Last, several peptides with high affinity to different integrins have been used for in vivo imaging. Ligands of αvβ3 integrin were used in the injured myocardium (79–81) or to monitor treatment effects after AMI (82). Upregulation is found not solely on activated myofibroblasts but also on macrophages (83) and activated endothelial cells of the microvasculature (84,85), limiting specificity for fibrotic processes. More recently, ligands for other integrin subtypes have been introduced (86), which may be helpful for more specific targeting of tissue fibrosis.

A Multimodal Imaging Toolbox for Characterization of Myocardial Fibrosis

In summary, all noninvasive cardiac imaging modalities have advanced to provide increasingly specific measures for the assessment of myocardial fibrosis. Of note, the modalities seem to be complementary to each other: although echocardiography is a readily available tool for serial assessment of ventricular remodeling and fibrosis-related systolic and diastolic dysfunction, it also provides measures of tissue stiffness via strain analysis. CMR can do the same, but it can also provide more accurate and detailed tissue characterization using methods that focus primarily on the composition of the extracellular space. Radionuclide-based molecular imaging adds information about the cellular component of fibrosis by providing measures of fibroblast activation and additional fibrosis-related signaling pathways. This complementarity may establish a comprehensive toolbox for noninvasive characterization of myocardial fibrosis.

Yet, some challenges remain to be resolved before a robust implementation in clinical trials and subsequent clinical practice: the precision and reproducibility of CMR and PET parameters need to be defined to determine usefulness for monitoring disease progression or treatment effects. CMR measures of tissue characterization may require a more thorough definition of multicenter repeatability and of the limits of detection of ECV expansion. PET imaging of FAP, on the other hand, is at a very early stage when compared with CMR. More information is required about repeatability; about the link between signal changes, disease progression, and outcome; and about its usefulness as a surrogate marker in clinical trials.

Table 4 highlights opportunities for a multimodal toolbox to contribute to progress in clinical cardiovascular precision medicine directed toward myocardial fibrosis.

View this table:
TABLE 4.

Ten Opportunities for Noninvasive Myocardial Fibrosis Imaging Techniques

FUTURE PERSPECTIVE: TOWARD FIBROSIS-TARGETED THERANOSTICS

It is likely that the relevance of modern fibrosis imaging tools will be defined by the success of novel antifibrotic therapies. As such, it is conducive that recent progress in imaging of cardiac fibrosis parallels the progress in understanding of cardiac fibrosis and the development of novel targeted antifibrotic interventions. The need for personalization and precision guidance of such novel therapies is strongly supported by the dynamic nature of fibrosis and the plasticity of the involved cells. Hence, future convergence of novel imaging biomarkers and therapies is to be expected. A powerful example is FAP, which has seen rapid development as a cardiac molecular imaging target (53) while, basically in parallel, an experimental approach for effective treatment of cardiac fibrosis by chimeric antigen receptor T cells targeted against FAP has been developed (12). Importantly, in a second step, a nanoparticle-based approach for transient in vivo FAP chimeric antigen receptor T-cell production has been introduced to address the temporal dynamics of fibrosis and to avoid unwanted long-term effects (20). Here, it is obvious that an imaging assay that identifies expression of the therapeutic target may be extremely helpful in guiding such sophisticated interventions to the most suitable individuals and the most suitable time. Accordingly, the concept of theranostics (87) may be applied to the future of cardiac fibrosis management—not just in the specific setting of FAP-targeted imaging and therapy but also in other settings where noninvasive fibrosis imaging provides actionable information for targeted antifibrotic therapy. Ideally, a fibrosis-targeted imaging assay provides one or more key parameters about the cellular or extracellular fibrosis burden and activity. Such markers may then be used in clinical trials to predict the likelihood of the success of a targeted antifibrotic therapy, and subsequent clinical practice would then use the imaging test for selection of suitable therapy candidates and for monitoring of the individual response, in a manner similar to theranostic approaches in oncology (e.g., for prostate cancer) or neurology (e.g., for amyloid-related neurodegenerative disease).

DISCLOSURE

This work was supported by the Leducq Foundation (Transatlantic Network “ImmunoFib HF”; Frank Bengel, Johanna Diekmann, and Annika Hess) and the German Research Foundation (Clinician Scientist Program “PRACTIS”; Johanna Diekmann). No other potential conflict of interest relevant to this article was reported.

Footnotes

  • Published online Nov. 1, 2023.

REFERENCES

  1. 1.↵
    1. de Boer RA,
    2. De Keulenaer G,
    3. Bauersachs J,
    4. et al
    . Towards better definition, quantification and treatment of fibrosis in heart failure. A scientific roadmap by the Committee of Translational Research of the Heart Failure Association (HFA) of the European Society of Cardiology. Eur J Heart Fail. 2019;21:272–285.
    OpenUrl
  2. 2.↵
    1. Heymans S,
    2. Gonzalez A,
    3. Pizard A,
    4. et al
    . Searching for new mechanisms of myocardial fibrosis with diagnostic and/or therapeutic potential. Eur J Heart Fail. 2015;17:764–771.
    OpenUrl
  3. 3.↵
    1. Frantz S,
    2. Hundertmark MJ,
    3. Schulz-Menger J,
    4. Bengel FM,
    5. Bauersachs J
    . Left ventricular remodelling post-myocardial infarction: pathophysiology, imaging, and novel therapies. Eur Heart J. 2022;43:2549–2561.
    OpenUrlCrossRef
  4. 4.↵
    1. Rurik JG,
    2. Aghajanian H,
    3. Epstein JA
    . Immune cells and immunotherapy for cardiac injury and repair. Circ Res. 2021;128:1766–1779.
    OpenUrlCrossRef
  5. 5.↵
    1. Travers JG,
    2. Kamal FA,
    3. Robbins J,
    4. Yutzey KE,
    5. Blaxall BC
    . Cardiac fibrosis: the fibroblast awakens. Circ Res. 2016;118:1021–1040.
    OpenUrlAbstract/FREE Full Text
  6. 6.↵
    1. Henderson NC,
    2. Rieder F,
    3. Wynn TA
    . Fibrosis: from mechanisms to medicines. Nature. 2020;587:555–566.
    OpenUrlCrossRef
  7. 7.↵
    1. López B,
    2. Gonzalez A,
    3. Ravassa S,
    4. et al
    . Circulating biomarkers of myocardial fibrosis: the need for a reappraisal. J Am Coll Cardiol. 2015;65:2449–2456.
    OpenUrlFREE Full Text
  8. 8.↵
    1. Jellis C,
    2. Martin J,
    3. Narula J,
    4. Marwick TH
    . Assessment of nonischemic myocardial fibrosis. J Am Coll Cardiol. 2010;56:89–97.
    OpenUrlFREE Full Text
  9. 9.↵
    1. González A,
    2. Schelbert EB,
    3. Diez J,
    4. Butler J
    . Myocardial interstitial fibrosis in heart failure: biological and translational perspectives. J Am Coll Cardiol. 2018;71:1696–1706.
    OpenUrlFREE Full Text
  10. 10.↵
    1. Ytrehus K,
    2. Hulot JS,
    3. Perrino C,
    4. Schiattarella GG,
    5. Madonna R
    . Perivascular fibrosis and the microvasculature of the heart. Still hidden secrets of pathophysiology? Vascul Pharmacol. April 27, 2018 [Epub ahead of print].
  11. 11.↵
    1. Wynn TA,
    2. Ramalingam TR
    . Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med. 2012;18:1028–1040.
    OpenUrlCrossRefPubMed
  12. 12.↵
    1. Aghajanian H,
    2. Kimura T,
    3. Rurik JG,
    4. et al
    . Targeting cardiac fibrosis with engineered T cells. Nature. 2019;573:430–433.
    OpenUrlCrossRefPubMed
  13. 13.↵
    1. Glasenapp A,
    2. Derlin K,
    3. Gutberlet M,
    4. et al
    . Molecular imaging of inflammation and fibrosis in pressure overload heart failure. Circ Res. 2021;129:369–382.
    OpenUrlCrossRef
  14. 14.↵
    1. Kuppe C,
    2. Ramirez Flores RO,
    3. Li Z,
    4. et al
    . Spatial multi-omic map of human myocardial infarction. Nature. 2022;608:766–777.
    OpenUrl
  15. 15.↵
    1. Lavine K,
    2. Amrute J,
    3. Luo X,
    4. et al
    . Targeting immune-fibroblast crosstalk in myocardial infarction and cardiac fibrosis. Research Square website. https://assets.researchsquare.com/files/rs-2402606/v1/b3540fa4cf7aff34b14af380.pdf?c=1674705715. Published 2023. Accessed September 27, 2023.
  16. 16.↵
    1. Tillmanns J,
    2. Hoffmann D,
    3. Habbaba Y,
    4. et al
    . Fibroblast activation protein alpha expression identifies activated fibroblasts after myocardial infarction. J Mol Cell Cardiol. 2015;87:194–203.
    OpenUrlCrossRef
  17. 17.↵
    1. Leask A,
    2. Abraham DJ
    . TGF-beta signaling and the fibrotic response. FASEB J. 2004;18:816–827.
    OpenUrlCrossRefPubMed
  18. 18.↵
    1. Zhao M,
    2. Wang L,
    3. Wang M,
    4. et al
    . Targeting fibrosis, mechanisms and clinical trials. Signal Transduct Target Ther. 2022;7:206.
    OpenUrl
  19. 19.↵
    1. McKinsey TA,
    2. Foo R,
    3. Anene-Nzelu CG,
    4. et al
    . Emerging epigenetic therapies of cardiac fibrosis and remodelling in heart failure: from basic mechanisms to early clinical development. Cardiovasc Res. 2023;118:3482–3498.
    OpenUrl
  20. 20.↵
    1. Rurik JG,
    2. Tombacz I,
    3. Yadegari A,
    4. et al
    . CAR T cells produced in vivo to treat cardiac injury. Science. 2022;375:91–96.
    OpenUrlCrossRefPubMed
  21. 21.↵
    1. Ajmone Marsan N,
    2. Delgado V,
    3. Shah DJ,
    4. et al
    . Valvular heart disease: shifting the focus to the myocardium. Eur Heart J. 2023;44:28–40.
    OpenUrl
  22. 22.↵
    1. Potter E,
    2. Marwick TH
    . Assessment of left ventricular function by echocardiography: the case for routinely adding global longitudinal strain to ejection fraction. JACC Cardiovasc Imaging. 2018;11:260–274.
    OpenUrlAbstract/FREE Full Text
  23. 23.↵
    1. Esch BT,
    2. Warburton DE
    . Left ventricular torsion and recoil: implications for exercise performance and cardiovascular disease. J Appl Physiol (1985). 2009;106:362–369.
    OpenUrlCrossRefPubMed
  24. 24.↵
    1. Buckberg G,
    2. Hoffman JI,
    3. Mahajan A,
    4. Saleh S,
    5. Coghlan C
    . Cardiac mechanics revisited: the relationship of cardiac architecture to ventricular function. Circulation. 2008;118:2571–2587.
    OpenUrlAbstract/FREE Full Text
  25. 25.↵
    1. Negishi T,
    2. Negishi K,
    3. Thavendiranathan P,
    4. et al
    . Effect of experience and training on the concordance and precision of strain measurements. JACC Cardiovasc Imaging. 2017;10:518–522.
    OpenUrlAbstract/FREE Full Text
  26. 26.↵
    1. Voigt JU,
    2. Pedrizzetti G,
    3. Lysyansky P,
    4. et al
    . Definitions for a common standard for 2D speckle tracking echocardiography: consensus document of the EACVI/ASE/Industry Task Force to standardize deformation imaging. Eur Heart J Cardiovasc Imaging. 2015;16:1–11.
    OpenUrlCrossRefPubMed
  27. 27.↵
    1. Stanton T,
    2. Leano R,
    3. Marwick TH
    . Prediction of all-cause mortality from global longitudinal speckle strain: comparison with ejection fraction and wall motion scoring. Circ Cardiovasc Imaging. 2009;2:356–364.
    OpenUrlAbstract/FREE Full Text
  28. 28.↵
    1. Zhang KW,
    2. French B,
    3. May Khan A,
    4. et al
    . Strain improves risk prediction beyond ejection fraction in chronic systolic heart failure. J Am Heart Assoc. 2014;3:e000550.
    OpenUrlAbstract/FREE Full Text
  29. 29.↵
    1. Hung CL,
    2. Verma A,
    3. Uno H,
    4. et al
    . Longitudinal and circumferential strain rate, left ventricular remodeling, and prognosis after myocardial infarction. J Am Coll Cardiol. 2010;56:1812–1822.
    OpenUrlFREE Full Text
  30. 30.↵
    1. Yingchoncharoen T,
    2. Gibby C,
    3. Rodriguez LL,
    4. Grimm RA,
    5. Marwick TH
    . Association of myocardial deformation with outcome in asymptomatic aortic stenosis with normal ejection fraction. Circ Cardiovasc Imaging. 2012;5:719–725.
    OpenUrlAbstract/FREE Full Text
  31. 31.↵
    1. Plana JC,
    2. Galderisi M,
    3. Barac A,
    4. et al
    . Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2014;27:911–939.
    OpenUrlCrossRefPubMed
  32. 32.↵
    1. Bull S,
    2. White SK,
    3. Piechnik SK,
    4. et al
    . Human non-contrast T1 values and correlation with histology in diffuse fibrosis. Heart. 2013;99:932–937.
    OpenUrlAbstract/FREE Full Text
  33. 33.↵
    1. de Jong S,
    2. Zwanenburg JJ,
    3. Visser F,
    4. et al
    . Direct detection of myocardial fibrosis by MRI. J Mol Cell Cardiol. 2011;51:974–979.
    OpenUrlCrossRefPubMed
  34. 34.↵
    1. Siu AG,
    2. Ramadeen A,
    3. Hu X,
    4. et al
    . Characterization of the ultrashort-TE (UTE) MR collagen signal. NMR Biomed. 2015;28:1236–1244.
    OpenUrl
  35. 35.↵
    1. Vandsburger M,
    2. Vandoorne K,
    3. Oren R,
    4. et al
    . Cardio-chemical exchange saturation transfer magnetic resonance imaging reveals molecular signatures of endogenous fibrosis and exogenous contrast media. Circ Cardiovasc Imaging. 2015;8:e002180.
    OpenUrlAbstract/FREE Full Text
  36. 36.↵
    1. Abdullah OM,
    2. Drakos SG,
    3. Diakos NA,
    4. et al
    . Characterization of diffuse fibrosis in the failing human heart via diffusion tensor imaging and quantitative histological validation. NMR Biomed. 2014;27:1378–1386.
    OpenUrl
  37. 37.↵
    1. Naser JA,
    2. Anupraiwan O,
    3. Adigun RO,
    4. et al
    . Myocardial stiffness by cardiac elastography in hypertrophic cardiomyopathy: relationship with myocardial fibrosis and clinical outcomes. JACC Cardiovasc Imaging. 2021;14:2051–2053.
    OpenUrl
  38. 38.↵
    1. Helm PA,
    2. Caravan P,
    3. French BA,
    4. et al
    . Postinfarction myocardial scarring in mice: molecular MR imaging with use of a collagen-targeting contrast agent. Radiology. 2008;247:788–796.
    OpenUrlCrossRefPubMed
  39. 39.↵
    1. Murphy AP,
    2. Greally E,
    3. O’Hogain D,
    4. Blamire A,
    5. Caravan P,
    6. Straub V
    . Noninvasive quantification of fibrosis in skeletal and cardiac muscle in mdx mice using EP3533 enhanced magnetic resonance imaging. Magn Reson Med. 2019;81:2728–2735.
    OpenUrl
  40. 40.↵
    1. Fontana M,
    2. White SK,
    3. Banypersad SM,
    4. et al
    . Comparison of T1 mapping techniques for ECV quantification. Histological validation and reproducibility of ShMOLLI versus multibreath-hold T1 quantification equilibrium contrast CMR. J Cardiovasc Magn Reson. 2012;14:88.
    OpenUrlCrossRefPubMed
  41. 41.↵
    1. Sado DM,
    2. Flett AS,
    3. Banypersad SM,
    4. et al
    . Cardiovascular magnetic resonance measurement of myocardial extracellular volume in health and disease. Heart. 2012;98:1436–1441.
    OpenUrlAbstract/FREE Full Text
  42. 42.↵
    1. Nacif MS,
    2. Kawel N,
    3. Lee JJ,
    4. et al
    . Interstitial myocardial fibrosis assessed as extracellular volume fraction with low-radiation-dose cardiac CT. Radiology. 2012;264:876–883.
    OpenUrlCrossRefPubMed
  43. 43.↵
    1. Landis CS,
    2. Li X,
    3. Telang FW,
    4. et al
    . Determination of the MRI contrast agent concentration time course in vivo following bolus injection: effect of equilibrium transcytolemmal water exchange. Magn Reson Med. 2000;44:563–574.
    OpenUrlCrossRefPubMed
  44. 44.↵
    1. Treibel TA,
    2. Kozor R,
    3. Schofield R,
    4. et al
    . Reverse myocardial remodeling following valve replacement in patients with aortic stenosis. J Am Coll Cardiol. 2018;71:860–871.
    OpenUrlFREE Full Text
  45. 45.↵
    1. Coelho-Filho OR,
    2. Shah RV,
    3. Mitchell R,
    4. et al
    . Quantification of cardiomyocyte hypertrophy by cardiac magnetic resonance: implications for early cardiac remodeling. Circulation. 2013;128:1225–1233.
    OpenUrlAbstract/FREE Full Text
  46. 46.↵
    1. Xia P,
    2. Chen J,
    3. Liu Y,
    4. Fletcher M,
    5. Jensen BC,
    6. Cheng Z
    . Doxorubicin induces cardiomyocyte apoptosis and atrophy through cyclin-dependent kinase 2-mediated activation of forkhead box O1. J Biol Chem. 2020;295:4265–4276.
    OpenUrlAbstract/FREE Full Text
  47. 47.↵
    1. López K,
    2. Neji R,
    3. Bustin A,
    4. et al
    . Quantitative magnetization transfer imaging for non-contrast enhanced detection of myocardial fibrosis. Magn Reson Med. 2021;85:2069–2083.
    OpenUrl
  48. 48.↵
    1. Niedermeyer J,
    2. Kriz M,
    3. Hilberg F,
    4. et al
    . Targeted disruption of mouse fibroblast activation protein. Mol Cell Biol. 2000;20:1089–1094.
    OpenUrlAbstract/FREE Full Text
  49. 49.
    1. Rettig WJ,
    2. Garin-Chesa P,
    3. Healey JH,
    4. et al
    . Regulation and heteromeric structure of the fibroblast activation protein in normal and transformed cells of mesenchymal and neuroectodermal origin. Cancer Res. 1993;53:3327–3335.
    OpenUrlAbstract/FREE Full Text
  50. 50.↵
    1. Park JE,
    2. Lenter MC,
    3. Zimmermann RN,
    4. Garin-Chesa P,
    5. Old LJ,
    6. Rettig WJ
    . Fibroblast activation protein, a dual specificity serine protease expressed in reactive human tumor stromal fibroblasts. J Biol Chem. 1999;274:36505–36512.
    OpenUrlAbstract/FREE Full Text
  51. 51.↵
    1. Altmann A,
    2. Haberkorn U,
    3. Siveke J
    . The latest developments in imaging of fibroblast activation protein. J Nucl Med. 2021;62:160–167.
    OpenUrlAbstract/FREE Full Text
  52. 52.↵
    1. Barton AK,
    2. Tzolos E,
    3. Bing R,
    4. et al
    . Emerging molecular imaging targets and tools for myocardial fibrosis detection. Eur Heart J Cardiovasc Imaging. 2023;24:261–275.
    OpenUrl
  53. 53.↵
    1. Diekmann J,
    2. Bengel FM
    . Cardiac applications of fibroblast activation protein imaging. PET Clin. 2023;18:389–396.
    OpenUrl
  54. 54.↵
    1. Mayola MF,
    2. Thackeray JT
    . The potential of fibroblast activation protein-targeted imaging as a biomarker of cardiac remodeling and injury. Curr Cardiol Rep. 2023;25:515–523.
    OpenUrl
  55. 55.↵
    1. Varasteh Z,
    2. Mohanta S,
    3. Robu S,
    4. et al
    . Molecular imaging of fibroblast activity after myocardial infarction using a 68Ga-labeled fibroblast activation protein inhibitor, FAPI-04. J Nucl Med. 2019;60:1743–1749.
    OpenUrlAbstract/FREE Full Text
  56. 56.↵
    1. Langer LBN,
    2. Hess A,
    3. Korkmaz Z,
    4. et al
    . Molecular imaging of fibroblast activation protein after myocardial infarction using the novel radiotracer [68Ga]MHLL1. Theranostics. 2021;11:7755–7766.
    OpenUrlCrossRef
  57. 57.↵
    1. Diekmann J,
    2. Koenig T,
    3. Zwadlo C,
    4. et al
    . Molecular imaging identifies fibroblast activation beyond the infarct region after acute myocardial infarction. J Am Coll Cardiol. 2021;77:1835–1837.
    OpenUrl
  58. 58.
    1. Kessler L,
    2. Kupusovic J,
    3. Ferdinandus J,
    4. et al
    . Visualization of fibroblast activation after myocardial infarction using 68Ga-FAPI PET. Clin Nucl Med. 2021;46:807–813.
    OpenUrl
  59. 59.↵
    1. Notohamiprodjo S,
    2. Nekolla SG,
    3. Robu S,
    4. et al
    . Imaging of cardiac fibroblast activation in a patient after acute myocardial infarction using 68Ga-FAPI-04. J Nucl Cardiol. 2022;29:2254–2261.
    OpenUrl
  60. 60.↵
    1. Diekmann J,
    2. Koenig T,
    3. Thackeray JT,
    4. et al
    . Cardiac fibroblast activation in patients early after acute myocardial infarction: integration with MR tissue characterization and subsequent functional outcome. J Nucl Med. 2022;63:1415–1423.
    OpenUrlAbstract/FREE Full Text
  61. 61.↵
    1. Heckmann MB,
    2. Reinhardt F,
    3. Finke D,
    4. et al
    . Relationship between cardiac fibroblast activation protein activity by positron emission tomography and cardiovascular disease. Circ Cardiovasc Imaging. 2020;13:e010628.
    OpenUrlCrossRef
  62. 62.↵
    1. Siebermair J,
    2. Kessler L,
    3. Kupusovic J,
    4. Rassaf T,
    5. Rischpler C
    . Cardiac fibroblast activation detected by 68gallium-FAPI-46 positron emission tomography-magnetic resonance imaging as a sign of chronic activity in cardiac sarcoidosis. Eur Heart J Case Rep. 2022;6:ytac005.
    OpenUrl
  63. 63.↵
    1. Guo W,
    2. Chen H
    . 68Ga FAPI PET/MRI in cardiac amyloidosis. Radiology. 2022;303:51.
    OpenUrl
  64. 64.↵
    1. Song W,
    2. Zhang X,
    3. He S,
    4. et al
    . 68Ga-FAPI PET visualize heart failure: from mechanism to clinic. Eur J Nucl Med Mol Imaging. 2023;50:475–485.
    OpenUrl
  65. 65.↵
    1. Treutlein C,
    2. Distler JHW,
    3. Tascilar K,
    4. et al
    . Assessment of myocardial fibrosis in patients with systemic sclerosis using [68Ga]Ga-FAPI-04-PET-CT. Eur J Nucl Med Mol Imaging. 2023;50:1629–1635.
    OpenUrl
  66. 66.↵
    1. Finke D,
    2. Heckmann MB,
    3. Herpel E,
    4. et al
    . Early detection of checkpoint inhibitor-associated myocarditis using 68Ga-FAPI PET/CT. Front Cardiovasc Med. 2021;8:614997.
    OpenUrl
  67. 67.↵
    1. Totzeck M,
    2. Siebermair J,
    3. Rassaf T,
    4. Rischpler C
    . Cardiac fibroblast activation detected by positron emission tomography/computed tomography as a possible sign of cardiotoxicity. Eur Heart J. 2020;41:1060.
    OpenUrlCrossRef
  68. 68.↵
    1. Diekmann J,
    2. Neuser J,
    3. Röhrich M,
    4. et al
    . Molecular imaging of myocardial fibroblast activation in patients with advanced aortic stenosis before transcatheter aortic valve replacement: a pilot study. J Nucl Med. 2023;64:1279–1286.
    OpenUrlAbstract/FREE Full Text
  69. 69.↵
    1. de Haas HJ,
    2. Arbustini E,
    3. Fuster V,
    4. Kramer CM,
    5. Narula J
    . Molecular imaging of the cardiac extracellular matrix. Circ Res. 2014;114:903–915.
    OpenUrlAbstract/FREE Full Text
  70. 70.↵
    1. Varasteh Z,
    2. Weber WA,
    3. Rischpler C
    . Nuclear molecular imaging of cardiac remodeling after myocardial infarction. Pharmaceuticals (Basel). 2022;15:183.
  71. 71.↵
    1. Muzard J,
    2. Sarda-Mantel L,
    3. Loyau S,
    4. et al
    . Non-invasive molecular imaging of fibrosis using a collagen-targeted peptidomimetic of the platelet collagen receptor glycoprotein VI. PLoS One. 2009;4:e5585.
    OpenUrlCrossRefPubMed
  72. 72.↵
    1. Zheng L,
    2. Ding X,
    3. Liu K,
    4. et al
    . Molecular imaging of fibrosis using a novel collagen-binding peptide labelled with 99mTc on SPECT/CT. Amino Acids. 2017;49:89–101.
    OpenUrl
  73. 73.↵
    1. Montesi SB,
    2. Izquierdo-Garcia D,
    3. Desogere P,
    4. et al
    . Type I collagen-targeted positron emission tomography imaging in idiopathic pulmonary fibrosis: first-in-human studies. Am J Respir Crit Care Med. 2019;200:258–261.
    OpenUrlCrossRefPubMed
  74. 74.↵
    1. Sahul ZH,
    2. Mukherjee R,
    3. Song J,
    4. et al
    . Targeted imaging of the spatial and temporal variation of matrix metalloproteinase activity in a porcine model of postinfarct remodeling: relationship to myocardial dysfunction. Circ Cardiovasc Imaging. 2011;4:381–391.
    OpenUrlAbstract/FREE Full Text
  75. 75.↵
    1. Su H,
    2. Spinale FG,
    3. Dobrucki LW,
    4. et al
    . Noninvasive targeted imaging of matrix metalloproteinase activation in a murine model of postinfarction remodeling. Circulation. 2005;112:3157–3167.
    OpenUrlAbstract/FREE Full Text
  76. 76.↵
    1. Dilsizian V,
    2. Eckelman WC,
    3. Loredo ML,
    4. Jagoda EM,
    5. Shirani J
    . Evidence for tissue angiotensin-converting enzyme in explanted hearts of ischemic cardiomyopathy using targeted radiotracer technique. J Nucl Med. 2007;48:182–187.
    OpenUrlAbstract/FREE Full Text
  77. 77.↵
    1. Verjans JW,
    2. Lovhaug D,
    3. Narula N,
    4. et al
    . Noninvasive imaging of angiotensin receptors after myocardial infarction. JACC Cardiovasc Imaging. 2008;1:354–362.
    OpenUrlAbstract/FREE Full Text
  78. 78.↵
    1. Fukushima K,
    2. Bravo PE,
    3. Higuchi T,
    4. et al
    . Molecular hybrid positron emission tomography/computed tomography imaging of cardiac angiotensin II type 1 receptors. J Am Coll Cardiol. 2012;60:2527–2534.
    OpenUrlFREE Full Text
  79. 79.↵
    1. Higuchi T,
    2. Bengel FM,
    3. Seidl S,
    4. et al
    . Assessment of alphavbeta3 integrin expression after myocardial infarction by positron emission tomography. Cardiovasc Res. 2008;78:395–403.
    OpenUrlCrossRefPubMed
  80. 80.
    1. Mandic L,
    2. Traxler D,
    3. Gugerell A,
    4. et al
    . Molecular imaging of angiogenesis in cardiac regeneration. Curr Cardiovasc Imaging Rep. 2016;9:27.
    OpenUrl
  81. 81.↵
    1. Makowski MR,
    2. Rischpler C,
    3. Ebersberger U,
    4. et al
    . Multiparametric PET and MRI of myocardial damage after myocardial infarction: correlation of integrin αvβ3 expression and myocardial blood flow. Eur J Nucl Med Mol Imaging. 2021;48:1070–1080.
    OpenUrl
  82. 82.↵
    1. Pfau D,
    2. Thorn SL,
    3. Zhang J,
    4. et al
    . Angiotensin receptor neprilysin inhibitor attenuates myocardial remodeling and improves infarct perfusion in experimental heart failure. Sci Rep. 2019;9:5791.
    OpenUrl
  83. 83.↵
    1. Antonov AS,
    2. Kolodgie FD,
    3. Munn DH,
    4. Gerrity RG
    . Regulation of macrophage foam cell formation by αVβ3 integrin: potential role in human atherosclerosis. Am J Pathol. 2004;165:247–258.
    OpenUrlCrossRefPubMed
  84. 84.↵
    1. Meoli DF,
    2. Sadeghi MM,
    3. Krassilnikova S,
    4. et al
    . Noninvasive imaging of myocardial angiogenesis following experimental myocardial infarction. J Clin Invest. 2004;113:1684–1691.
    OpenUrlCrossRefPubMed
  85. 85.↵
    1. Jenkins WS,
    2. Vesey AT,
    3. Stirrat C,
    4. et al
    . Cardiac αVβ3 integrin expression following acute myocardial infarction in humans. Heart. 2017;103:607–615.
    OpenUrlAbstract/FREE Full Text
  86. 86.↵
    1. Steiger K,
    2. Quigley NG,
    3. Groll T,
    4. et al
    . There is a world beyond αvβ3-integrin: multimeric ligands for imaging of the integrin subtypes αvβ6, αvβ8, αvβ3, and α5β1 by positron emission tomography. EJNMMI Res. 2021;11:106.
    OpenUrl
  87. 87.↵
    1. Weber WA,
    2. Barthel H,
    3. Bengel F,
    4. Eiber M,
    5. Herrmann K,
    6. Schafers M
    . What is theranostics? J Nucl Med. 2023;64:669–670.
    OpenUrlFREE Full Text
  88. 88.
    1. Puls M,
    2. Beuthner BE,
    3. Topci R,
    4. et al
    . Impact of myocardial fibrosis on left ventricular remodelling, recovery, and outcome after transcatheter aortic valve implantation in different haemodynamic subtypes of severe aortic stenosis. Eur Heart J. 2020;41:1903–1914.
    OpenUrlCrossRefPubMed
  89. 89.
    1. Díez J,
    2. Querejeta R,
    3. Lopez B,
    4. Gonzalez A,
    5. Larman M,
    6. Martinez Ubago JL
    . Losartan-dependent regression of myocardial fibrosis is associated with reduction of left ventricular chamber stiffness in hypertensive patients. Circulation. 2002;105:2512–2517.
    OpenUrlAbstract/FREE Full Text
  90. 90.
    1. Yamagami K,
    2. Oka T,
    3. Wang Q,
    4. et al
    . Pirfenidone exhibits cardioprotective effects by regulating myocardial fibrosis and vascular permeability in pressure-overloaded hearts. Am J Physiol Heart Circ Physiol. 2015;309:H512–H522.
    OpenUrlCrossRefPubMed
  91. 91.
    1. Van Aelst LN,
    2. Voss S,
    3. Carai P,
    4. et al
    . Osteoglycin prevents cardiac dilatation and dysfunction after myocardial infarction through infarct collagen strengthening. Circ Res. 2015;116:425–436.
    OpenUrlAbstract/FREE Full Text
  92. 92.
    1. Purcell BP,
    2. Barlow SC,
    3. Perreault PE,
    4. et al
    . Delivery of a matrix metalloproteinase-responsive hydrogel releasing TIMP-3 after myocardial infarction: effects on left ventricular remodeling. Am J Physiol Heart Circ Physiol. 2018;315:H814–H825.
    OpenUrl
  93. 93.
    1. Suthahar N,
    2. Meijers WC,
    3. Sillje HHW,
    4. Ho JE,
    5. Liu FT,
    6. de Boer RA
    . Galectin-3 activation and inhibition in heart failure and cardiovascular disease: an update. Theranostics. 2018;8:593–609.
    OpenUrlCrossRefPubMed
  • Received for publication June 20, 2023.
  • Revision received September 25, 2023.
View Abstract
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Bookmark this article

Jump to section

Keywords