Myocardial fibrosis is a key healing response after myocardial infarction driven by activated fibroblasts. Gallium-68-labeled fibroblast activation protein inhibitor ([68Ga]-FAPI) is a novel positron-emitting radiotracer that binds activated fibroblasts. The aim of this study was to investigate the intensity, distribution, and time-course of fibroblast activation after acute myocardial infarction. A total of 40 patients with acute myocardial infarction underwent hybrid [68Ga]FAPI-46 positron emission tomography and cardiac magnetic resonance and were compared with matched control subjects (n = 19) and those with chronic (>2 years) myocardial infarction (n = 20). Intensity of [68Ga]FAPI-46 uptake was quantified by maximum target-to-background ratio (TBRmax). Burdens of fibroblast activation and scar were assessed by percent myocardial involvement of [68Ga]FAPI-46 uptake and late gadolinium enhancement, respectively. Myocardial [68Ga]FAPI-46 uptake was observed in the acute infarct and peri-infarct regions that exceeded the extent of late gadolinium enhancement (burden 27.8% ± 12.4% vs 15.2% ± 10.6%; P < 0.001). One-third of patients also demonstrated right ventricular involvement. Myocardial [68Ga]FAPI-46 uptake was most intense at 1 and 2 weeks before declining at 4 and 12 weeks (TBRmax 4.0 ± 1.1, 3.7 ± 1.0, 3.1 ± 0.8, and 2.7 ± 0.7; P < 0.001). In comparison with control subjects, increased [68Ga]FAPI-46 uptake was observed in chronic (7 ± 6 years ago) infarcts at lower intensity than acute infarction (TBRmax 1.2 ± 0.1 vs 1.7 ± 0.5 vs 4.0 ± 1.1; P < 0.001). Baseline [68Ga]FAPI-46 burden correlated with lower left ventricular ejection fraction (r = -0.606), higher indexed left ventricular end-diastolic volume (r = 0.572), and higher scar burden (r = 0.871) at 1 year (P < 0.001 for all). Increased remote myocardial [68Ga]FAPI-46 uptake was associated with left ventricular dilatation and systolic dysfunction. Myocardial fibroblast activation peaks within a week of acute myocardial infarction and extends beyond the infarct region. It declines slowly with time, persists for years, and is associated with subsequent left ventricular remodeling. (PROFILE-MI-The FAPI Fibrosis Study; NCT05356923).

BACKGROUND Myocardial fibrosis is a key healing response after myocardial infarction driven by activated fibroblasts. Gallium-68-labeled fibroblast activation protein inhibitor ([68Ga]-FAPI) is a novel positron-emitting radiotracer that binds activated fibroblasts. OBJECTIVES The aim of this study was to investigate the intensity, distribution, and time-course of fibroblast activation after acute myocardial infarction. METHODS A total of 40 patients with acute myocardial infarction underwent hybrid [68Ga]FAPI-46 positron emission tomography and cardiac magnetic resonance and were compared with matched control subjects (n = 19) and those with chronic (>2 years) myocardial infarction (n = 20). Intensity of [68Ga]FAPI-46 uptake was quantified by maximum target- to-background ratio (TBRmax). Burdens of fibroblast activation and scar were assessed by percent myocardial involvement of [68Ga]FAPI-46 uptake and late gadolinium enhancement, respectively. RESULTS Myocardial [68Ga]FAPI-46 uptake was observed in the acute infarct and peri-infarct regions that exceeded the extent of late gadolinium enhancement (burden 27.8% f 12.4% vs 15.2% f 10.6%; P < 0.001). One-third of patients also demonstrated right ventricular involvement. Myocardial [68Ga]FAPI-46 uptake was most intense at 1 and 2 weeks before declining at 4 and 12 weeks (TBRmax 4.0 f 1.1, 3.7 f 1.0, 3.1 f 0.8, and 2.7 f 0.7; P < 0.001). In comparison with control subjects, increased [68Ga]FAPI-46 uptake was observed in chronic (7 f 6 years ago) infarcts at lower intensity than acute infarction (TBRmax 1.2 f 0.1 vs 1.7 f 0.5 vs 4.0 f 1.1; P < 0.001). Baseline [68Ga]FAPI-46 burden correlated with lower left ventricular ejection fraction (r =-0.606), higher indexed left ventricular end-diastolic volume (r = 0.572), and higher scar burden (r = 0.871) at 1 year (P < 0.001 for all). Increased remote myocardial [68Ga]FAPI-46 uptake was associated with left ventricular dilatation and systolic dysfunction. CONCLUSIONS Myocardial fibroblast activation peaks within a week of acute myocardial infarction and extends beyond the infarct region. It declines slowly with time, persists for years, and is associated with subsequent left ventricular remodeling. (PROFILE-MI-The FAPI Fibrosis Study; NCT05356923) (JACC. 2025;85:578-591) (c) 2025 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Abstract Background Novel molecular positron emission tomography (PET) assessments of fibrosis are now available but have not been compared directly to cardiovascular magnetic resonance (CMR), the current reference standard for myocardial scar assessment. Using 68Gallium-fibroblast activation protein inhibitor (FAPI), a radiotracer that binds to activated fibroblasts, we compared CMR and PET assessments of myocardial scar following ST-elevation myocardial infarction. Methods Hybrid 68Ga-FAPI-46 PET/MR with gadolinium-based contrast agent was performed in 40 patients within 4 weeks of acute ST-elevation myocardial infarction (acute STEMI) with 19 returning at 12 weeks for repeat PET/MR (subacute STEMI). Scar burden (%LGE) was measured on late enhancement short axis CMR images (Circle Cardiovascular Imaging software, Canada). Volume and intensity of global myocardial 68Ga-FAPI uptake was quantified (QPET, Cedars Sinai, Los Angeles) to determine the volume myocardium with tracer uptake (%68Ga-FAPI) and intensity of PET signal (target-to-background ratio, TBRmax) after correcting for right atrial blood-pool activity. Results In acute STEMI, high intensity uptake of 68Ga-FAPI was observed localized to the infarct. The area of fibroblast activation greatly exceeded the area of scar detected by late gadolinium enhancement (LGE) (%68Ga-FAPI 26.6+-15.4% vs 14.5+-11.4%, p<0.001). 68Ga-FAPI volume and intensity declined between acute and subacute STEMI (%68Ga-FAPI 26.6+-15.4% vs 12.8+-8.1%, p<0.001, TBRmax 3.9+-1.1 vs 2.7+-0.7, p<0.001). By week 12, there was no difference between the area of fibroblast activation detected by 68Ga-FAPI uptake and area of scar detected by LGE (%68Ga-FAPI 12.8+-8.1% vs %LGE 10.3+-6.1%, ns). Conclusion Molecular PET assessments of myocardial scar formation provide different but complementary information to structural assessments of myocardial scar. Fibroblast activation following myocardial infarction is a dynamic process that can be non-invasively measured for the first time by 68Ga-FAPI PET.

Fibrosis is one of the key healing responses to injury, especially within the heart where it helps to maintain structural integrity following acute insults such as myocardial infarction. However, if it becomes dysregulated then fibrosis can become maladaptive leading to adverse remodelling, impaired cardiac function and heart failure. Fibroblast activation protein is exclusively expressed by activated fibroblasts, the key effector cells of fibrogenesis, and has a unique extracellular domain that is an ideal ligand for novel molecular imaging probes. Fibroblast activation protein inhibitor (FAPI) radiotracers have been developed for PET imaging, demonstrating high selectivity for activated fibroblasts across a range of different pathologies and disparate organ systems. In this review, we will summarize the role of fibroblast activation protein in cardiovascular disease and how FAPI radiotracers might improve the assessment and treatment of patients with cardiovascular diseases.

Activated fibroblasts drive leaflet thickening and left ventricular decompensation in aortic stenosis. Gallium-68 Fibroblast Activation Protein Inhibitor (68Ga-FAPI) binds to these key effector cells, and provides a readout of fibroblast activation. We aimed to describe the role of activated fibroblasts in patients with aortic stenosis in vivo using 68Ga-FAPI. In a prospective observational study, patients with aortic stenosis and control subjects underwent echocardiography, 68Ga-FAPI PET, CT, and MRI. Valvular and myocardial 68Ga-FAPI uptake was quantified using maximal standardised uptake values (SUVmax), and target-to-background ratio (TBRmax). Aortic stenosis severity was measured by peak velocity on echocardiography and the CT calcium score. Myocardial fibrosis was quantified by late gadolinium enhancement (LGE) on MRI. 86 patients with aortic valve disease (72±11 years, 68% male) plus 9 matched control subjects (72±9 years, 67%% male) participated. Increased 68Ga-FAPI uptake was observed in the aortic valves of patients with aortic stenosis compared with controls (p<0.001). 68Ga-FAPI TBRmax correlated with peak velocity (r=0.532, p<0.0010) and calcium score (r = 0.577, p<0.001). 54 patients (69%) had myocardial 68Ga-FAPI uptake, of whom 30 (38%) also had LGE corresponding to the region of 68Ga-FAPI uptake. Myocardial 68Ga-FAPI uptake correlated with increased indexed left ventricular mass (r=0.429, p<0.001) and indexed Extracellular Volume (r=0.404, p<0.001). For the first time, we have described valvular and myocardial fibroblast activation in patients with aortic stenosis in vivo. Valvular fibroblast activation is increased in patients with aortic stenosis, correlating with increased disease severity. Myocardial fibroblast activation is seen in the majority of patients with aortic stenosis in areas with and without established fibrosis, and is associated with adverse left ventricular remodelling. 68Ga-FAPI PET can visualise the key effector cell driving aortic valve disease, and may have a role in monitoring disease modifying treatments, as well as identifying patients at high risk of myocardial decompensation. Please click on the 'PDF' for the full abstract!

Introduction: Spatial transcriptomics has become a powerful tool for interrogating a disease-specific transcriptome within the context of tissue architecture. In this study, we used spatial transcriptomics to investigate the molecular mechanisms underlying COVID-19 in the lungs and heart. Methods: We performed sequencing-based spatial transcriptomics (ST), using 10X Genomics’ Visium, on 6 paired fatal COVID-19 lung and heart tissue samples and 2 control samples per organ. With the gene by spot matrix, we performed dimensional reduction, clustering (Louvain), differential expression (Wilcoxon Rank sum test), and pathway analysis (GSEA). spacexr was used to estimate the cell type composition of ST spots. Results: By histology and ST, COVID-19 tissue was defined by a loss in parenchymal cells and increased inflammation ( fig. 1E ). In both the heart and lung, we found a cluster of ST spots specific to fatal COVID-19 ( fig. 1A, B ; P<0.001). Between the two organs, these clusters shared genes and pathways relating to tissue remodeling, B cell action, and complement pathway activation ( fig. 1C, D ). Response to wounding and blood vessel endothelial cell migration pathways were distinct to the heart cluster, also explaining the increased capillary cell weight in the COVID-19 heart compared to the control ( fig. 1D, E ; P=0.0167). Conclusion: Our results suggest that there is a shared spatial niche between the heart and lungs in COVID-19 infection and highlight the importance of studying multiple organs in understanding the disease. These findings provide new insights into the molecular basis of COVID-19 and have the potential to inform the development of novel therapies for this disease. Figure 1 (A) UMAP colored by (left) clusters and (right) disease. (B) Cluster proportions between COVID-19 and control tissue (C) Scatter plot of shared differentially expressed genes. (D) GSEA pathway score. (E) Spatial mapping of clusters and cell-type deconvolution.

Abstract Background Myocardial fibrosis following myocardial infarction (MI) is a key healing mechanism and involves widespread fibroblast activation. Once activated, fibroblasts express fibroblast activation protein (FAP) (1). Hybrid positron emission tomography (PET) imaging of radiolabelled fibroblast activation protein inhibitor (FAPI) fused with cardiovascular magnetic resonance (68Ga-FAPI PET/MR) is an emerging method for assessing myocardial fibrosis activity that may provide additional insights into the recovery of the heart following MI. Methods Forty patients with acute (<4 weeks), 19 with recent (12 weeks), and 19 with prior established ST-segment elevation MI (>12 months), and 20 healthy volunteer participants underwent 68Ga-FAPI PET/MR. Participants were imaged 30 min after administration of 100-200 MBq 68Ga-FAPI-04. Image analysis was performed using FusionQuant (Cedars Sinai, Los Angeles, California). 68Ga-FAPI uptake was quantified by maximum standardised uptake value (SUVmax) and tissue-to-background ratio (TBRmax) correcting for blood-pool activity in the left ventricle. Comparisons between were assessed with one-way ANOVA with Tukey-Kramer post-hoc testing where significant differences were detected. A 2-sided p-value of <0.05 denoted statistical significance. Results Participants were predominantly middle-aged men with similar sized infarcts (peak plasma cardiac troponin concentrations and post-MI left ventricular ejection fraction) (Table). Blood pool tracer activity was also similar between groups. Focal myocardial 68Ga-FAPI uptake localised to areas of the infarct and peri-infarct zones on magnetic resonance late gadolinium enhancement imaging (Figure). Both myocardial SUVmax and TBRmax varied between infarcts of different ages, being highest in acute (TBRmax 4.1±1.2) and lowest in those with prior established MI (2.1±0.7, Table and Figure). Conclusions Fibrosis activity is greatest in the immediate aftermath of acute MI with a step-wise reduction in the weeks and years that follow. Fibrosis activity continues for many months and years after acute infarction.FigureTable

BackgroundAlthough myocardial fibrosis can be quantified by magnetic resonance (MR), assessment of fibrosis activity is important as this will inform disease activity and the presence of ongoing adverse cardiac remodelling. Fibroblast activation protein (FAP) is expressed on the surface of activated myofibroblasts and is a marker of ongoing fibrosis activity. Radiolabelled FAP-specific ligands, such as 68-Gallium (68Ga)-FAP inhibitor (FAPI), represent a promising new approach to quantify fibrosis activity in the myocardium.PurposeTo investigate whether 68Ga-FAPI positron emission tomography (PET)/MR can detect myocardial fibrosis activity in patients with heart failure with reduced ejection fraction.MethodsIn a prospective cross-sectional study, patients with heart failure with reduced ejection fraction and healthy volunteers underwent 68Ga-FAPI PET/MR. 10 patients had repeat imaging at 6 months. Standardised uptake values (SUVmax) and tissue to background ratios (TBR) were calculated within the left ventricular (LV) wall.ResultsParticipants were predominantly middle-aged men: patients with heart failure (n=45; median age 65 [60-74] years, 76% male) and healthy volunteers (59 [56-62] years,70% male). LV ejection fraction was reduced in patients with heart failure (40±8%) but was normal in healthy volunteers (60±6%; P<0.001). Within the heart failure cohort, 22 patients had ischaemic cardiomyopathy and 23 patients had non-ischaemic cardiomyopathy. Compared with healthy volunteers, patients with heart failure had higher myocardial uptake of 68Ga-FAPI (SUVmax 3.2±1.5 versus 1.5±0.3, p<0.001; TBR 1.9±0.8 versus 1.1±0.2, p<0.001; Figure 1). Myocardial 68Ga-FAPI uptake was higher in patients with either ischaemic or non-ischaemic cardiomyopathy compared to healthy volunteers (SUVmax 4.0±1.7 and 2.3±0.5 versus 1.5±0.3 respectively; p<0.001 for both) and was higher in patients with ischaemic compared to non-ischaemic cardiomyopathy (p<0.001). Differential patterns of 68Ga-FAPI uptake were also observed with increased LV uptake seen particularly in the basal septum of patients with non-ischaemic cardiomyopathy and in the infarct zone of patients with ischaemic cardiomyopathy (Figure 2). Based on the Youden’s index of the receiver-operator curves, the optimal threshold for identifying myocardial fibrosis in patients with heart failure was SUVmax of 1.9 with a specificity of 90%, sensitivity of 89% and area under the curve of 0.94. At 6 months, 68Ga-FAPI uptake was unchanged in the 10 patients with chronic heart failure that underwent repeat scanning (p=0.91).ConclusionIncreased myocardial fibrosis activity can be detected with 68Ga-FAPI PET/MR in patients with heart failure. Differential patterns of 68Ga-FAPI uptake are seen in patients with non-ischaemic cardiomyopathy or ischaemic cardiomyopathy. This may help characterise and prognosticate patients with heart failure and inform the future development of novel heart failure therapies.Conflict of InterestNone

AbstractMyocardial fibrosis is the heart’s common healing response to injury. While initially seeking to optimize the strength of diseased tissue, fibrosis can become maladaptive, producing stiff poorly functioning and pro-arrhythmic myocardium. Different patterns of fibrosis are associated with different myocardial disease states, but the presence and quantity of fibrosis largely confer adverse prognosis. Current imaging techniques can assess the extent and pattern of myocardial scarring, but lack specificity and detect the presence of established fibrosis when the window to modify this process may have ended. For the first time, novel molecular imaging methods, including gallium-68 (68Ga)-fibroblast activation protein inhibitor positron emission tomography (68Ga-FAPI PET), may permit highly specific imaging of fibrosis activity. These approaches may facilitate earlier fibrosis detection, differentiation of active vs. end-stage disease, and assessment of both disease progression and treatment–response thereby improving patient care and clinical outcomes.

Abstract Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): British Heart Foundation - Prof Marc Dweck Senior Fellowship, and BHF Research Excellence Award 3 for Dr Anna K Barton. Background Myocardial fibrosis is a key healing response following myocardial infarction (MI). Although scar formation following MI is considered complete by 12 weeks, its exact time course is unknown. Fibroblast activation protein is a key factor in fibrogenesis that is expressed by activated fibroblasts in the myocardium following MI. Hybrid positron emission tomography and cardiovascular magnetic resonance (PET/MR) with radiolabelled fibroblast activation protein inhibitor (68Ga-FAPI) is an emerging method to measure in vivo fibrosis activity. Purpose To investigate the timing of myocardial fibrosis activity following ST-elevation MI using 68Ga-FAPI PET/MR Methods Twenty patients underwent multi-timepoint hybrid 68Ga-FAPI PET/MR <1, 2, 4, and 12 weeks following acute ST-elevation MI. They were compared to patients with prior established ST-elevation MI (>12 months) and healthy controls who underwent single-timepoint 68Ga-FAPI PET/MR to determine fibrosis activity in chronic infarcts and healthy myocardium respectively. All participants were imaged 30 min following administration of 100–200 MBq 68Ga-FAPI-04. Infarct zone 68Ga-FAPI uptake was quantified using tissue-to-background ratio (TBRmax) after correction for blood-pool activity in the left ventricle. Comparisons between timepoints for the acute MI group were assessed by ANOVA with repeated measures and post hoc Bonferroni correction, and between groups by two-tailed t-test. Results Participants were predominantly middle-aged men (Table). Focal 68Ga-FAPI uptake localised to areas of infarction within the infarct and peri-infarct zones on late gadolinium enhancement on magnetic resonance imaging (Figure). In acute MI, there was substantial uptake with consistent TBRmax values at weeks 1, 2 and 4 (Table and Figure). Though TBRmax values started to decline by week 12 they remained persistently elevated compared to prior established MI and healthy myocardium (Table). Participants with prior established MI had modestly increased 68Ga-FAPI uptake compared with the healthy myocardium of control participants (Table and Figure). Conclusions Intense myocardial fibrosis activity is observed in the infarct and peri-infarct zones throughout the first month following ST-elevation MI. Although this starts to decline by 12 weeks, it remains markedly elevated even several years after myocardial infarction, indicating that low-level chronic fibroblast activity is a feature of established MI.

A range of novel lipid‐lowering agents are now available, providing options for patients unable to achieve sufficient control on older drugs such as statins. This article gives an overview of the main lipid‐lowering agents, their indications and usage, with a focus on the newer therapies targeting PCSK9.