Translocator Protein 18 kDa Tracer 18F-FDPA PET/CTA Imaging for the Evaluation of Inflammation in Vulnerable Plaques.

Inflammation induced by activated macrophages within vulnerable atherosclerotic plaques (VAPs) constitutes a significant risk factor for plaque rupture. Translocator protein (TSPO) is highly expressed in activated macrophages. This study investigated the effectiveness of TSPO radiotracers, 18F-FDPA, in detecting VAPs and quantifying plaque inflammation in rabbits. 18 New Zealand rabbits were divided into 3 groups: sham group A, VAP model group B, and evolocumab treatment group C. 18F-FDPA PET/CTA imaging was performed at 12, 16, and 24 weeks in all groups. Optical coherence tomography (OCT) was performed on the abdominal aorta at 24 weeks. The VAP was defined through OCT images, and ex vivo aorta PET imaging was also performed at 24 weeks. The SUVmax and SUVmean of 18F-FDPA were measured on the target organ, and the target-to-background ratio (TBRmax) was calculated as SUVmax/SUVblood pool. The arterial sections of the isolated abdominal aorta were analyzed by HE staining, CD68 and TSPO immunofluorescence staining, and TSPO Western blot. The results showed that at 24 weeks, the plaque TBRmax of 18F-FDPA in group B was significantly higher than in groups A and C. Immunofluorescence staining of CD68 and TSPO, as well as Western blot, confirmed the increased expression of macrophages and TSPO in the corresponding regions of group B. HE staining revealed an increased presence of the lipid core, multiple foam cells, and inflammatory cell infiltration in the area with high 18F-FDPA uptake. This indicates a correlation between 18F-FDPA uptake, inflammation severity, and VAPs. The TSPO-targeted tracer 18F-FDPA shows specific uptake in macrophage-rich regions of atherosclerotic plaques, making it a valuable tool for assessing inflammation in VAPs.

Coronary sodium [18F]fluoride activity predicts outcomes post-CABG: a comparative evaluation with conventional metrics.

PURPOSE: The value of preoperative multidisciplinary approach remains inadequately delineated in forecasting postoperative outcomes of patients undergoing coronary artery bypass grafting (CABG). Herein, we aimed to ascertain the efficacy of multi-modality cardiac imaging in predicting post-CABG cardiovascular outcomes. METHODS: Patients with triple coronary artery disease underwent cardiac sodium [18F]fluoride ([18F]NaF) positron emission tomography/computed tomography (PET/CT), coronary angiography, and CT-based coronary artery calcium scoring before CABG. The maximum coronary [18F]NaF activity (target-to-blood ratio [TBR]max) and the global coronary [18F]NaF activity (TBRglobal) was determined. The primary endpoint was perioperative myocardial infarction (PMI) within 7-day post-CABG. Secondary endpoint included major adverse cardiac and cerebrovascular events (MACCEs) and recurrent angina. RESULTS: This prospective observational study examined 101 patients for a median of 40 months (interquartile range: 19-47 months). Both TBRmax (odds ratio [OR] = 1.445; p = 0.011) and TBRglobal (OR = 1.797; P = 0.018) were significant predictors of PMI. TBRmax>3.0 (area under the curve [AUC], 0.65; sensitivity, 75.0%; specificity, 56.8%; p = 0.036) increased PMI risk by 3.661-fold, independent of external confounders. Kaplan-Meier test revealed a decrease in MACCE survival rate concomitant with an escalating TBRmax. TBRmax>3.6 (AUC, 0.70; sensitivity, 76.9%; specificity, 73.9%; p = 0.017) increased MACCEs risk by 5.520-fold. Both TBRmax (hazard ratio [HR], 1.298; p = 0.004) and TBRglobal (HR = 1.335; p = 0.011) were significantly correlated with recurrent angina. No significant associations were found between CAC and SYNTAX scores and between PMI occurrence and long-term MACCEs. CONCLUSION: Quantification of coronary microcalcification activity via [18F]NaF PET displayed a strong ability to predict early and long-term post-CABG cardiovascular outcomes, thereby outperforming conventional metrics of coronary macrocalcification burden and stenosis severity. TRIAL REGISTRATION: The trial was registered with the Chinese Clinical Trial Committee (number: ChiCTR1900022527; URL: www.chictr.org.cn/showproj.html?proj=37933 ).

Reduced hematopoietic-inflammatory response and worse outcomes in patients with recurrent myocardial infarction in comparison with primary myocardial infarction.

BACKGROUND: Recurrent myocardial infarction (RMI) portends an unfavorable outcome, which might be related to diminished hematopoietic-inflammatory activation. We aimed to investigate the hematopoietic-inflammatory activation and the outcome in categorized patients with primary myocardial infarction (PMI) versus RMI as well as chronic stable angina (CSA) by 18F-FDG PET. RESULTS: A total of 105 patients (88 males; 60.1 ± 9.7 years) were included. Target-to-background ratio of bone marrow (TBRBM) was highest in the PMI group (n = 45), intermediate in the RMI group (n = 30), and lowest in the CSA group (n = 30) (P < 0.001). RMI group exhibited larger scar, significantly reduced left ventricular ejection fraction, and enlarged end systolic volume in comparison with the PMI and CSA groups, respectively (P < 0.05). Additionally, there was a significantly positive correlation between TBRBM and TBRaorta (P < 0.001). The cumulative major adverse cardiac events free survival of patients in the RMI group was lower than that in the PMI and CSA groups during a median follow-up of 16.6 months (P = 0.026). CONCLUSIONS: RMI conferred relatively decreased hematopoietic-inflammatory activation compared with PMI. Patients with RMI presented subsequent enlarged myocardial scar, worsened cardiac dysfunction, aggravated remodeling, and worse outcomes than that in PMI patients.

In Vivo Coronary 18F-Sodium Fluoride Activity: Correlations With Coronary Plaque Histological Vulnerability and Physiological Environment.

BACKGROUND: 18F-sodium fluoride (18F-NaF) positron emission tomography (PET)/computed tomography (CT) is a promising new approach for assessing microcalcification in vascular plaque. OBJECTIVES: This prospective study aimed to evaluate the associations between in vivo coronary 18F-NaF PET/CT activity and ex vivo histological characteristics, to determine whether coronary 18F-NaF activity is a novel biomarker of plaque pathological vulnerability, and to explore the underlying physiological environment of 18F-NaF adsorption to vascular microcalcification. METHODS: Patients with coronary artery disease (CAD) underwent coronary computed tomography angiography (CTA) and 18F-NaF PET/CT. Histological vulnerability and immunohistochemical characteristics were evaluated in coronary endarterectomy (CE) specimens from patients who underwent coronary artery bypass grafting with adjunctive CE. Correlations between in-vivo coronary 18F-NaF activity with coronary CTA adverse plaque features and with ex vivo CE specimen morphological features, CD68 expression, inflammatory cytokines expression (tumor necrosis factor-α, interleukin-1ß), osteogenic differentiation cytokines expression (osteopontin, runt-related transcription factor 2, osteocalcin) were evaluated. High- and low- to medium-risk plaques were defined by standard pathological classification. RESULTS: A total of 55 specimens were obtained from 42 CAD patients. Coronary 18F-NaF activity of high-risk specimens was significantly higher than low- to medium-risk specimens (median [25th-75th percentile]: 1.88 [1.41-2.54] vs 1.12 [0.91-1.54]; P < 0.001). Coronary 18F-NaF activity showed high discriminatory accuracy in identifying high-risk plaque (AUC: 0.80). Coronary CTA adverse plaque features (positive remodeling, low-attenuation plaque, remodeling index), histologically vulnerable features (large necrotic core, thin-fibro cap, microcalcification), CD68 expression, tumor necrosis factor-α expression, and interleukin-1ß expression correlated with coronary 18F-NaF activity (all P < 0.05). No significant association between coronary 18F-NaF activity and osteogenic differentiation cytokines was found (all P > 0.05). CONCLUSIONS: Coronary 18F-NaF activity was associated with histological vulnerability, CD68 expression, inflammatory cytokines expression, but not with osteogenic differentiation cytokines expression. 18F-NaF PET/CT imaging may provide a powerful tool for detecting high-risk coronary plaque and could improve the risk stratification of CAD patients.

Metformin confers longitudinal cardiac protection by preserving mitochondrial homeostasis following myocardial ischemia/reperfusion injury.

PURPOSE: Myocardial ischemia-reperfusion (I/R) injury is associated with systemic oxidative stress, cardiac mitochondrial homeostasis, and cardiomyocyte apoptosis. Metformin has been recognized to attenuate cardiomyocyte apoptosis. However, the longitudinal effects and pathomechanism of metformin on the regulation of myocardial mitohormesis following I/R treatment remain unclear. This study aimed to investigate the longitudinal effects and mechanism of metformin in regulating cardiac mitochondrial homeostasis by serial imaging with the 18-kDa translocator protein (TSPO)-targeted positron emission tomography (PET) tracer 18F-FDPA. METHODS: Myocardial I/R injury was established in Sprague-Dawley rats, which were treated with or without metformin (150 mg/kg per day). Serial gated 18F-FDG and 18F-FDPA PET imaging were performed at 1, 4, and 8 weeks after surgery, followed by analysis of ventricular remodelling and cardiac mitochondrial homeostasis. The correlation between Hsp60 and 18F-FDPA uptake was analyzed. After PET imaging, the activity of antioxidant enzymes, immunostaining, and western blot analysis were performed to analyze the spatio-temporal effects and pathomechanism of metformin for cardiac protection after myocardial I/R injury. RESULTS: Oxidative stress and apoptosis increased 1 week after myocardial I/R injury (before significant progression of ventricular remodelling). TSPO expression was correlated with Hsp60 expression and was co-localized with inflammatory CD68+ macrophages in the infarct area, and TSPO uptake was associated with an upregulation of AMPK-p/AMPK and a downregulation of Bcl-2/Bax. However, these effects were reversed with metformin treatment. Eight weeks after myocardial I/R injury (representing the advanced stage of heart failure), 18F-FDPA uptake in myocardial cells in the distal non-infarct area increased without CD68+ expression, whereas the activity decreased with metformin treatment. CONCLUSION: Taken together, these results show that a prolonged metformin treatment has pleiotropic protective effects against myocardial I/R injury associated with a regional and temporal dynamic balance between mitochondrial homeostasis and cardiac outcome, which were assessed by TSPO-targeted imaging during cardiac remodelling.

Neurometabolism and Ventricular Dyssynchrony in Patients With Heart Failure and Reduced Ejection Fraction.

BACKGROUND: The brain coordinates the heart through the autonomic nervous system (ANS). Numerous mediator signals along the brain-heart axis interact with the neuronal-metabolic system in heart failure (HF). Disturbances in cardio-neural interactions influence the disease progression in patients with HF. OBJECTIVES: The purpose of this study was to investigate the interactome between ANS-associated neurometabolism and ventricular dyssynchrony in patients with heart failure with reduced ejection fraction (HFrEF). Further, we studied the association of neurometabolism with major arrhythmic events (MAEs). METHODS: A total of 197 patients with HFrEF who underwent gated single-photon emission computed tomography myocardial perfusion imaging and the brain 18F-fluorodeoxyglucose positron emission tomography/computed tomography were prospectively enrolled. Relationships between the brain metabolism and MAEs were assessed using Cox models and mediation analyses. Finally, metabolic central autonomic networks were constructed and statistically compared between patients with and without MAEs. RESULTS: In total, 35 (17.8%) patients experienced MAEs during a median follow-up of 3.1 years. In patients with HFrEF (age 58 years [IQR: 50-64 years], left ventricular ejection fraction: 20.0% [IQR: 15.0%-25.0%]), glucose hypometabolism in the insula, hippocampus, amygdala, cingulate gyrus, and caudate nucleus were independent predictors for MAEs (all P < 0.05). Cerebral hypometabolism was related to ventricular dyssynchrony, which was the predominant risk factor of MAEs. Additionally, patients who experienced MAEs presented hypoconnectivity in the metabolic central autonomic network compared with those without MAEs (P < 0.05). CONCLUSIONS: We found an interaction of the neuronal metabolic-ventricular dyssynchronization axis in HF, which might be related to MAEs. This new brain-heart axis could expand our understanding of the distinct pathomechanisms of HFrEF.

Associations between coronary/aortic 18F-sodium fluoride uptake and pro-atherosclerosis factors in patients with multivessel coronary artery disease.

BACKGROUND: 18F-NaF PET/CT is a novel approach to detect and quantify microcalcification in atherosclerosis. We aimed to explore the underlying systematic vascular osteogenesis in the coronary artery and aorta in patients with multivessel coronary artery disease (CAD). METHODS: Patients with multivessel CAD prospectively underwent 18F-NaF PET/CT. The coronary microcalcification activity (CMA) and aortic microcalcification activity (AMA) were calculated based on both the volume and intensity of 18F-NaF PET activity. Peri-coronary adipose tissue (PCAT) density was measured in adipose tissue surrounding the coronary arteries and the 18F-NaF tissue-to-blood ratio (TBR) was measured in the coronary arteries. RESULTS: 100 patients with multivessel CAD were prospectively recruited. The CMA was significantly associated with the AMA (r = 0.70; P < .001). After multivariable adjustment, the CMA was associated with the AMA (Beta = 0.445 per SD increase; P < .001). The coronary TBR was also significantly associated with the PCAT density (r = 0.56; P < .001). The PCAT density was independently associated with the coronary TBR after adjusting confounding factors. CONCLUSIONS: Coronary 18F-NaF uptake was significantly associated with the PCAT density. There was a significant relationship between the coronary and the aortic 18F-NaF uptake. It might indicate an underlying systematic vascular osteogenesis in patients with multivessel CAD.

Transient cardioprotective effects of remote ischemic postconditioning on non-reperfused myocardial infarction: longitudinal evaluation study in pigs.

BACKGROUND: Remote ischemic postconditioning (RIPostC) has recently emerged as a potential novel therapeutic strategy to achieve protection against acute myocardial infarction (AMI) injury. We aimed to evaluate the longitudinal cardioprotective effects of RIPostC on AMI using 99mTc-MIBI SPECT myocardial perfusion imaging (MPI) and gated 18F-FDG PET (GPET) in pigs. METHODS: MI was induced in 12 Chinese pigs. RIPostC was conducted by four 5 min cycles of blood pressure cuff inflation applied to the lower limb immediately after AMI. MPI and GPET were performed longitudinally at baseline, 3rd, 14th, 28th, and 56th days after AMI. Total perfusion defect (TPD), hibernating myocardium (HM), scar, left ventricular (LV) remodeling (End diastolic volume, EDV), and bone marrow (BM) metabolic activity were analyzed, and inflammation biomarkers were measured. RESULTS: In outcome evaluation, there was a significant attenuation in TPD (Δ value, at 14th, 28th and 56th days), HM (Δ value, at 14th, 56th days) and Scar (Δ value, at 14th, 28th days) in the RIPostC group compared with the control group (P < 0.05). Additionally, RIPostC attenuated LV enlargement (ΔEDV, at 14th day) (P < 0.05) in comparison to controls. BM 18F-FDG uptake activity in the RIPostC group was lower than the control group (P < 0.05) at the 3rd day after AMI. There was a non-statistically significant trend of decreased MMP-2 levels in the RIPostC group post-AMI (P > 0.05). CONCLUSIONS: RIPostC presented the longitudinal cardioprotective effects by preserving myocardial viability, reducing infarct size, attenuating LV remodeling at early stage post-AMI, and may also have an anti-inflammatory effect at the acute phase.

Assessment of cerebral glucose metabolism in patients with heart failure by 18F-FDG PET/CT imaging.

BACKGROUND: To evaluate the cerebral metabolism in patients with heart failure (HF). METHODS: One hundred and two HF patients were prospectively enrolled, who underwent gated 99mTc-sestamibi single photon emission computed tomography (SPECT)/CT, cardiac and cerebral 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT. Fifteen healthy volunteers served as controls. Patients were stratified by extent of hibernating myocardium (HM) and left ventricular ejection fraction (LVEF) into 4 groups where Group1: HM < 10% (n = 33); Group2: HM ≥ 10%, LVEF < 25% (n = 34); Group3: HM ≥ 10%, 25% ≤ LVEF ≤ 40% (n = 16) and Group 4: LVEF > 40% (n = 19). The standardized uptake value (SUV) in the whole brain (SUVwhole-brain) and the SUV ratios (SUVR) in 24 cognition-related brain regions were determined. SUVwhole-brain and SUVRs were compared between the 4 patient groups and the healthy controls. RESULTS: SUVwhole-brain (r = 0.245, P = 0.013) and SUVRs in frontal areas, hippocampus, and para-hippocampus (r: 0.213 to 0.308, all P < 0.05) were correlated with HM. SUVwhole-brain differed between four patient groups and the healthy volunteers (P = 0.016) and SUVwhole-brain in Group 1 was lower than that in healthy volunteers (P < 0.05). SUVRs of Group 3 in frontal areas were the highest among four patient subgroups (P < 0.05). CONCLUSIONS: Cerebral metabolism in the whole brain was reduced but maintained in cognition-related frontal areas in HF patients with HM and moderately impaired global left ventricular function.

Detection of aortic prosthetic graft infection with 18F-FDG PET/CT imaging, concordance with consensus MAGIC graft infection criteria.

OBJECTIVES: The aim of this study was to investigate the diagnostic yield of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) for detecting thoracic aortic graft infection (AGI) in comparison to expert consensus MAGIC criteria. METHODS: Patients suspected clinically of having thoracic-AGI were prospectively recruited. Consensus MAGIC criteria for AGI were compared to findings on FDG PET imaging. MAGIC criteria were verified against clinical/surgical, radiological, and microbiological/laboratory predefined major and minor parameters. FDG images were interpreted using a semiquantitative visual grading score (VGS, abnormal ≥ 3), focal uptake and quantitative maximum standard FDG uptake value (SUVmax, abnormal ≥ 7.3), and target-to-background FDG ratio (TBRmax, abnormal ≥ 4.2). RESULTS: Of 35 patients suspected of having thoracic-AGI, MAGIC diagnostic criteria were positive for AGI in 25 patients (71%) and negative in 10 (29%). FDG PET imaging was abnormal in 27 patients (77%). Abnormal and normal FDG imaging findings were concordant with MAGIC criteria in 31 patients (88.6%). In 4 patients, FDG imaging results were discordant with MAGIC criteria. By ROC analysis, optimal FDG cut-off values for detecting AGI by MAGIC were ≥ 3 for VGS, ≥ 7.3 for SUVmax and ≥ 4.2 for TBRmax, with concordance with MAGIC criteria in 88.6%, 85.7%, and 88.6% of patients, respectively. Two or more FDG imaging parameters (VGS, focal uptake, SUVmax, and TBRmax) yielded highest diagnostic concordance of 91.4%. VGS inverse odds ratio for AGI was 7.14. In 4 of 6 selective patients who had repeat FDG PET imaging during antibiotic treatment, quantitative FDG imaging values improved over time with associated improvement of laboratory markers of inflammation. CONCLUSIONS: FDG PET/CT imaging, using (semi-)quantitative imaging parameters, showed high concordance with expert consensus MAGIC criteria for AGI. These data suggest a potential complementary role of quantitative FDG/CT imaging, not only to detect AGI, but also to monitor response to antibiotic treatment.

Automated synthesis and preliminary evaluation of [18F]FDPA for cardiac inflammation imaging in rats after myocardial infarction.

A translocator protein 18 kDa targeted radiotracer, N,N-diethyl-2-(2-(4-[18F]fluorophenyl)-5,7-dimethylpyrazolo[1,5-a] pyrimidin-3-yl) acetamide ([18F]FDPA), was automated synthetized and evaluated for cardiac inflammation imaging. Various reaction conditions for an automated synthesis were systematically optimized. MicroPET/CT imaging were performed on normal rats and rats with myocardial infarction (MI). Normalized SUV ratios of [18F]FDPA to [13N]NH3 (NSRs) in different regions were calculated to normalize the uptake of [18F]FDPA to perfusion. The amount of TBAOMs and the volume/proportion of water were crucial for synthesis. After optimization, the total synthesis time was 68 min. The non-decay corrected radiochemical yields (RCYs) and molar activities were 19.9 ± 1.7% and 169.7 ± 46.5 GBq/µmol, respectively. In normal rats, [18F]FDPA showed a high and stable cardiac uptake and fast clearance from other organs. In MI rats, NSRs in the peri-infarct and infarct regions, which were infiltrated with massive inflammatory cells revealed by pathology, were higher than that in the remote region (1.20 ± 0.01 and 1.08 ± 0.10 vs. 0.89 ± 0.05, respectively). [18F]FDPA was automated synthesized with high RCYs and molar activities. It showed a high uptake in inflammation regions and offered a wide time window for cardiac imaging, indicating it could be a potential cardiac inflammation imaging agent.

[Principle and implementation of list-mode image reconstruction in PET].

Positron emission tomography (PET) has become basic support equipment in clinical and many other scientific research fields and has been a hot research field at present. Tomography reconstruction algorithm is a key component of PET, and most PETs use statistical iterative reconstruction algorithms from sinograms data currently. However, tomography reconstruction from list-mode data possesses many unique advantages, and it has caused great attention and is in the process of rapid development and improvementin recently. We eventually achieved list-mode tomography reconstruction in this paper, using experimental data of small animal PET scanner Eplus-166, exploiting S-LMEM algorithm and orthogonal distance-based ray-tracer. The results demonstrated that image resolution and contrast recovery achieved inherent properties of the scanner and on-the-fly ray-tracing methods is feasible for dynamic reconstruction.