Tissue-level evidence of fibroblast activation protein inhibitor imaging in hypertrophic obstructive cardiomyopathy: a case series.

Background: Myocardial fibrosis is a key pathological factor for the occurrence of ventricular arrhythmias in hypertrophic obstructive cardiomyopathy (HOCM). Case summary: This case series reports on two patients diagnosed with HOCM who underwent 18F-fibroblast activation protein inhibitor (FAPI) positron-emission tomography/computed tomography imaging and Morrow myotomy procedure. The collected myocardial tissue was examined histopathologically. Both patients exhibited intense and heterogeneous 18F-FAPI uptake in the septum, with significant number of activated fibroblasts. Discussion: Enhanced 18F-FAPI uptake was observed before irreversible fibrosis, and the degree of 18F-FAPI uptake was higher in tissue with greater fibrosis. 18F-FAPI imaging may provide a promising tool for guiding surgical strategy in HOCM, and further research is needed to fully explore its potential in clinical practice.

Fibroblast activation protein imaging in atrial fibrillation: a proof-of-concept study.

BACKGROUND: To evaluate the feasibility of using radiolabeled fibroblast activation protein inhibitor (FAPI) PET/CT imaging to assess activated fibroblasts in the atria of individuals with AF and to identify factors contributing to enhanced atrial activity. METHODS: We constructed left atrial appendage (LAA) pacing beagle dog AF models (n = 5) and conducted 18F-FAPI PET/CT imaging at baseline and eight weeks after pacing. Right atrial (RA) specimens were collected from these models. Additionally, 28 AF patients and ten age- and sex-matched healthy volunteers underwent 18F-FAPI PET/CT imaging. RESULTS: RA of AF beagles showed increased 18F-FAPI uptake. Among AF patients, 18 out of 28 (64.3%) exhibited enhanced atrial FAPI activity. No atrial 18F-FAPI uptake was observed in the sham beagle and healthy volunteers. In animal RA specimens, 18F-FAPI activity correlated positively with FAP mRNA (r = .98, P = .002) and protein (r = .82, P = .03) levels, as well as collagen I mRNA expression (r = .85, P = .02). B-type natriuretic peptide levels were associated with atrial 18F-FAPI activity (OR = 3.01, P = .046). CONCLUSION: This proof-of-concept study suggests that 18F-FAPI PET/CT imaging may be a feasible method for evaluating activated fibroblasts in the atria of AF patients.

Functional significance of myocardial activity at 18F-FAPI PET/CT in hypertrophic cardiomyopathy identified by cardiac magnetic resonance feature-tracking strain analysis.

PURPOSE: This study aimed to evaluate the functional significance of 18F-labeled fibroblast activation protein inhibitor (18F-FAPI) activity in hypertrophic cardiomyopathy (HCM) by comparison with cardiac magnetic resonance feature-tracking (CMR-FT) strain analysis. METHODS: A total of 49 HCM patients were included in this study. Two independent control groups of healthy participants with a matched age and sex to the HCM patients were also enrolled. Left ventricular (LV) 18F-FAPI activity was analyzed for extent (FAPI%) and intensity (maximum target-to-background ratio, TBRmax). The CMR tissue characterization parameters of the LV included late gadolinium enhancement, native T1 value, and extracellular volume fraction. LV strain analysis was performed in radial, circumferential, and longitudinal peak strains (PS). RESULTS: Intense LV myocardial 18F-FAPI uptake was observed in HCM patients, whereas no obvious uptake was detected in healthy participants (median TBRmax, 9.1 vs. 1.2, p < 0.001). The strain parameters of HCM patients, compared with healthy participants, were significantly impaired (mean radial PS, 23.5 vs. 36.0, mean circumferential PS, -14.5 vs. -20.0, and mean longitudinal PS, -9.9 vs. -16.0, all p < 0.001). At segmental levels, there was a moderate correlation between 18F-FAPI activity and strain parameters. The number of positive 18F-FAPI uptake segments (n = 653) was higher than that of hypertrophic segments (n = 190) and positive CMR tissue characterization segments (n = 525) (all p < 0.001). In segments with negative CMR tissue characterization findings, the strain capacity of positive 18F-FAPI uptake segments was lower than that of negative 18F-FAPI uptake segments (median radial PS, 30.5 vs. 36.1, p = 0.026 and median circumferential PS, -18.4 vs. -19.7, p = 0.041). CONCLUSION: 18F-FAPI imaging can partially reflect the potential strain reduction in HCM patients. 18F-FAPI imaging detects more involved myocardium than CMR tissue characterization techniques, and the additionally identified myocardium has impaired strain capacity.

Myocardial Activity at 18F-FAPI PET/CT and Risk for Sudden Cardiac Death in Hypertrophic Cardiomyopathy.

Background Myocardial fibrosis contributes to adverse cardiovascular events in hypertrophic cardiomyopathy (HCM). Purpose To explore the characteristics of cardiac fibroblast activation protein inhibitor (FAPI) PET/CT imaging and its relationship with the risk of sudden cardiac death (SCD) in HCM. Materials and Methods In this prospective study from July 2021 to January 2022, participants with HCM and healthy control participants underwent cardiac fluorine 18 (18F)-labeled FAPI PET/CT imaging. Myocardial FAPI activity was quantified as intensity (target-to-background uptake ratio), extent (the percent of FAPI-avid myocardium of the left ventricle [LV]), and amount (the percent of FAPI-avid myocardium of LV × target-to-background ratio). Regional wall thickness was analyzed at cardiac MRI. The 5-year SCD risk score was calculated from the 2014 European Society of Cardiology guidelines. Univariable and multivariable linear regression analyses were used to identify factors related to the FAPI amount. The correlation between FAPI amount and 5-year SCD risk was explored. Results Fifty study participants with HCM (mean age, 43 years ± 13 [SD]; 32 men) and 22 healthy control participants (mean age, 45 years ± 17; 14 men) were included. All participants with HCM had intense and inhomogeneous cardiac FAPI activity in the LV myocardium that was higher than that in healthy control participants (median target-to-background ratio, 8.8 vs 2.1, respectively; P < .001). In HCM, more segments with FAPI activity were detected than the number of hypertrophic segments (median, 14 vs five, respectively; P < .001); 84% of nonhypertrophic segments showed FAPI activity. Log-transformed FAPI amount had a positive relationship with log-transformed N-terminal probrain natriuretic peptide, high-sensitive troponin I, and left atrial diameter and a negative relationship with LV ejection fraction z-score. Degree of FAPI activity positively correlated with the 5-year SCD risk score (r = 0.32; P = .03). Conclusion Fibroblast activation protein inhibitor (FAPI) PET/CT imaging indicated intense and heterogeneous activity in hypertrophic cardiomyopathy, and FAPI uptake was associated with 5-year risk of sudden cardiac death. © RSNA, 2022 Online supplemental material is available for this article.

Pulmonary artery imaging with 68 Ga-FAPI-04 in patients with chronic thromboembolic pulmonary hypertension.

BACKGROUND: The feasibility and significance of imaging pulmonary artery (PA) remodeling with 68 Ga-fibroblast activating protein inhibitor (FAPI) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) have not yet been addressed. METHODS: 68 Ga-FAPI-04 uptake in the PA and ascending artery was evaluated in 13 patients with CTEPH and 13 matched non-CTEPH controls. The correlations of PA 68 Ga-FAPI-04 uptake and remodeling parameters derived from right heart catheterization (RHC) were analyzed. RESULTS: Of the 13 patients with CTEPH, nine (69%) showed visually enhanced 68 Ga-FAPI-04 uptake, whereas none of the control subjects had increased 68 Ga-FAPI-04 uptake in the PA. The prevalence of enhanced uptake in the main, lobar, and segmental PAs was 45% (17/38), 33% (16/48), and 28% (44/159), respectively. 68 Ga-FAPI-04 activity in the PA was positively correlated with pulmonary arterial diastolic pressure (r = 0.571, P = 0.041). CONCLUSION: 68 Ga-FAPI-04 has the potential for imaging fibroblast activation in the PA wall, and 68 Ga-FAPI-04 activity in PA is positively correlated with pulmonary arterial diastolic pressure.

Association of atrial 18F-fluorodeoxyglucose uptake and prior ischemic stroke in non-atrial fibrillation patients.

BACKGROUND: Atrial cardiomyopathy has gained increasing attention in the field of ischemic stroke due to its prothrombotic substrate. Timely identification of high-risk individuals without atrial fibrillation (AF) is essential in secondary prevention. We sought to explore the feasibility of atrial 18F-fluorodeoxyglucose (FDG) imaging in detecting diseased atrial substrate and in identifying ischemic stroke in a non-AF population. METHODS: 1444 non-AF inpatients were initially identified. Among them, 196 patients had enhanced atrial FDG uptake, while 392 patients without atrial activity were selected as controls. Atrial activity, the history of ischemic stroke, and atrial cardiomyopathy were analyzed. RESULTS: Patients with atrial cardiomyopathy had a higher prevalence of enhanced atrial activity (47.1% vs 26.0%, P < .001), and patients with increased atrial activity had a higher prevalence of a prior history of ischemic stroke (12.2% vs 3.3%, P < .001). Multivariate regression analysis demonstrated that atrial activity was independently related to ischemic stroke after adjustment for risk factors (OR 4.02, 95% CI 1.97-8.19, P < .001) and atrial cardiomyopathy (OR 3.63, 95% CI 1.51-8.74, P = .004). CONCLUSIONS: This study identified an association between atrial FDG activity and a history of ischemic stroke and atrial cardiomyopathy in non-AF individuals. Further longitudinal study is warranted to demonstrate their causal relationship.

Fibroblast activation protein imaging in reperfused ST-elevation myocardial infarction: comparison with cardiac magnetic resonance imaging.

PURPOSE: The aim of this study was to explore the correlation of 18F-labeled fibroblast activation protein inhibitor (FAPI) and cardiovascular magnetic resonance (CMR) parameters in ST-elevation myocardial infarction (STEMI) patients with successful primary percutaneous coronary intervention (PPCI) and to investigate the value of FAPI imaging in predicting cardiac functional recovery, as well as the correlation between FAPI activity and circulating fibroblast activation protein (FAP) and inflammatory biomarkers. METHODS: Fourteen first-time STEMI patients (11 men, mean age: 62 ± 11 years) after PPCI and 14 gender-matched healthy volunteers (10 men, mean age: 50 ± 14 years) who had completed FAPI imaging and blood sample collection were prospectively recruited. All patients underwent baseline FAPI imaging (6 ± 2 days post-MI) and CMR (8 ± 2 days post-MI). Ten patients had follow-up CMR (84 ± 4 days post-MI). Myocardial FAPI activity was analyzed for extent (the percentage of FAPI uptake volume over the left ventricular volume, FAPI%), intensity (target-to-background uptake ratio, TBRmax), and amount (FAPI% × TBRmax). Late gadolinium enhancement (LGE), T2-weighted imaging (T2WI), extracellular volume (ECV), microvascular obstruction (MVO), and cardiac function from CMR imaging were analyzed. Blood samples obtained on the day of FAPI imaging were used to assess circulating FAP, TGF-ß1, TNF-α, IL-6, and hsCRP in STEMI patients and controls. RESULTS: Localized but inhomogeneous FAPI uptake was observed in STEMI patients, which was larger than the edematous and infarcted myocardium, whereas no uptake was detected in controls. The MVO area showed lower FAPI uptake compared with the surrounding myocardium. FAPI activity was associated with the myocardial injury biomarkers T2WI, LGE, and ECV at both per-patient and per-segment levels (all p < 0.05), but was not associated with circulating FAP, TGF-ß1, TNF-α, IL-6, or hsCRP. Among the CMR parameters, T2WI had the greatest correlation coefficient with both FAPI% and FAPI% × TBRmax. Baseline TBRmax was inversely correlated with the follow-up left ventricular ejection fraction (LVEF) (r = - 0.73, p = 0.02). CONCLUSION: FAPI imaging detects more involved myocardium than CMR in reperfused STEMI, and is associated with myocardial damage and follow-up LVEF.

Imaging of cardiac fibroblast activation in patients with chronic thromboembolic pulmonary hypertension.

PURPOSE: The aim of this study was to explore the association of cardiac fibroblast activation with clinical parameters and cardiovascular magnetic resonance (CMR) imaging parameters in patients with chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: Thirteen CTEPH patients were prospectively enrolled. All of the patients underwent cardiac 68Gallium-labelled fibroblast activation protein inhibitor (68 Ga-FAPI-04)-positron emission tomography/computed tomography (PET/CT), right heart catheterisation, and echocardiography, and 11 of them additionally underwent CMR. Thirteen control subjects were selected to establish the normal range of cardiac 68 Ga-FAPI-04 uptake. Cardiac 68 Ga-FAPI-04 uptake higher than that in the blood pool was defined as abnormal. The global and segmental maximum standardised uptake values (SUVmax) of the right ventricle (RV) were measured and further expressed as target-to-background ratio (TBRRV) with left ventricular lateral wall activity as background. Late gadolinium enhancement (LGE) was visually evaluated, and native-T1 times, enhanced-T1 times, and extracellular volume (ECV) were quantitatively measured. RESULTS: Ten CTEPH patients (77%) had abnormal 68 Ga-FAPI-04 uptake in RV, mainly located in the free wall, which was significantly higher than that in controls (TBRRV: 2.4 ± 0.9 vs 1.0 ± 0.1, P < 0.001). The TBRRV correlated positively with the thickness of RV wall (r = 0.815, P = 0.001) and inversely with RV fraction area change (RVFAC) (r = - 0.804, P = 0.001) and tricuspid annular plane systolic excursion (TAPSE) (r = - 0.678, P = 0.011). No correlation was found between 68 Ga-FAPI-04 activity and CMR imaging parameters. CONCLUSION: Fibroblast activation in CTEPH, measured by 68 Ga-FAPI-04 imaging, is mainly localised in the RV free wall. Enhanced fibroblast activation reflects the thickening of the RV wall and decreased RV contractile function.

Association of Serum Biomarkers and Cardiac Inflammation in Patients With Atrial Fibrillation: Identification by Positron Emission Tomography.

Background: Peripheral biomarkers may be affected by various factors, their reliability in reflecting local cardiac inflammatory status in patients with atrial fibrillation (AF) needs further exploration. This prospective study was aimed to investigate the relationship between circulating biomarkers and local cardiac inflammation measured by epicardial adipose tissue (EAT) activity via 18F-fluorodeoxyglucose (FDG) imaging in AF patients. Methods: From 2017 to 2018, 83 AF patients [43 persistent AF (PsAF) and 40 paroxysmal AF (PAF)] referred for radiofrequency catheter ablation (RFCA) were recruited. Pre- and post-RFCA blood samples were collected to measure IL-6, IL-8, IL-10, IL-18, TNF-α, Hsp27, Hsp60, Hsp70, PDGF-BB, MMP-2, MMP-9, MPO, TGF-ß1, Gal-3, and sST2. Pre-RFCA FDG images were obtained to assess EAT activity. Sixty-seven patients (35 PAF and 32 PsAF) received RFCA were regularly followed for 27 (24, 29) months. Results: Higher hsCRP and IL-6 and lower TGF-ß1 were demonstrated in PsAF patients compared with PAF patients. Multivariate logistic regression analysis demonstrated that Gal-3 (OR: 1.221, 95% CI: 1.024-1.456, P = 0.026) and MPO (OR: 1.002, 95% CI: 1.001-1.003, P = 0.027) were independently correlated with EAT activity. The percentage decrease of Hsp60 linearly correlated with that of EAT activity post-RFCA (Spearman r s = 0.455, P = 0.019). Seventeen patients (10 PsAF and 7 PAF) had AF recurrence, but none of the selected biomarkers were predictive of post-RFCA recurrence. Conclusion: Our findings demonstrated that in patients with AF, Gal-3 correlated with local cardiac inflammation, and Hsp60 was associated with the alleviation of cardiac inflammation after RFCA.

18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging in atrial fibrillation: a pilot prospective study.

AIMS: This prospective study explored relevant factors and clinical significance of atrial 18F-fluorodeoxyglucose (FDG) uptake in patients with atrial fibrillation (AF). METHODS AND RESULTS: One hundred AF patients underwent baseline FDG imaging prior to radiofrequency catheter ablation (RFCA). Of those, 30 subjects underwent additional FDG imaging at 3 months post-RFCA. Voltage mapping of the left atrium was analysed as a voltage score. Patients who received RFCA were followed for 26 months (17-31 months) to assess recurrence. At baseline FDG imaging, 74% of patients with persistent AF (PsAF) and 24% of patients with paroxysmal AF showed increased atrial FDG uptake. The prevalence was higher in the right atrium (49%) than in the left atrium (15%, P < 0.001) or left atrial appendage (21%, P < 0.001). Multivariate analysis demonstrated that PsAF and elevated B-type natriuretic peptide (BNP) were related to enhanced right atrial (RA) activity, and increased epicardial adipose tissue (EAT) activity was predictive of left atrial (LA) activity. LA activity was inversely associated with voltage score, while increased FDG uptake in the right atrium was predictive of successful AF termination by RFCA. Atrial FDG activities decreased significantly post-RFCA, but none of the FDG parameters were predictive of AF recurrence. CONCLUSIONS: Enhanced RA activity was associated with elevated BNP level, whereas LA activity was related to the increased activity of EAT and inversely correlated with LA fibrosis. Increased RA activity was predictive of successful AF termination by RFCA in PsAF patients.

Factors relevant to atrial 18F-fluorodeoxyglucose uptake in atrial fibrillation.

BACKGROUND: This retrospective study was designed to explore the factors relevant to increased atrial 18F-fluorodeoxyglucose (FDG) uptake in patients with atrial fibrillation (AF) who had undergone routine whole-body positron emission tomography/computed tomography (PET/CT) imaging. METHODS AND RESULTS: Forty-eight consecutive AF patients (32 persistent, 16 paroxysmal) were identified from our routine FDG PET/CT database. Twenty-two control subjects were selected to establish the normal range of FDG uptake (maximum standardized uptake value, SUVmax) in target tissues. A target-to-background ratio (TBR) was calculated to determine abnormal uptake in the atrium and atrial appendage (AA). Univariate comparisons and multivariate regression analyses were conducted to explore the factors associated with the increased FDG accumulation in the atrium and AA. Seventeen AF patients, all with persistent AF, had increased atrial FDG uptake. Most of them (14, or 82.4%) had increased uptake in the right atrium. Eleven AF patients, 9 with persistent AF, had increased uptake in the AA, and bilateral AAs were equally involved. Multivariate logistic regression analyses identified that female gender, persistent AF, and activity in epicardial adipose tissue (EAT) were independent factors predicting the increased activity of the atrium; also, SUVmax of the left ventricle was found for the AA. In addition, multivariate linear regression analyses showed that EAT activity was the only independent variable linearly correlated with the activity of the atrium and AA. CONCLUSIONS: Atrial uptake was present in persistent AF and localized mainly in the right atrium, whereas bilateral AAs could be equally involved. Multiple factors contributed to the increased activity in atrium; in particular, the EAT activity was independently correlated with the activity of the atrium and AA.