Comparing various AI approaches to traditional quantitative assessment of the myocardial perfusion in [82Rb] PET for MACE prediction.

Assessing the individual risk of Major Adverse Cardiac Events (MACE) is of major importance as cardiovascular diseases remain the leading cause of death worldwide. Quantitative Myocardial Perfusion Imaging (MPI) parameters such as stress Myocardial Blood Flow (sMBF) or Myocardial Flow Reserve (MFR) constitutes the gold standard for prognosis assessment. We propose a systematic investigation of the value of Artificial Intelligence (AI) to leverage [ 82 Rb] Silicon PhotoMultiplier (SiPM) PET MPI for MACE prediction. We establish a general pipeline for AI model validation to assess and compare the performance of global (i.e. average of the entire MPI signal), regional (17 segments), radiomics and Convolutional Neural Network (CNN) models leveraging various MPI signals on a dataset of 234 patients. Results showed that all regional AI models significantly outperformed the global model ( p < 0.001 ), where the best AUC of 73.9% (CI 72.5-75.3) was obtained with a CNN model. A regional AI model based on MBF averages from 17 segments fed to a Logistic Regression (LR) constituted an excellent trade-off between model simplicity and performance, achieving an AUC of 73.4% (CI 72.3-74.7). A radiomics model based on intensity features revealed that the global average was the least important feature when compared to other aggregations of the MPI signal over the myocardium. We conclude that AI models can allow better personalized prognosis assessment for MACE.

Cardiac PET Myocardial Blood Flow Quantification Assessment of Early Cardiac Allograft Vasculopathy.

BACKGROUND: Positron emission tomography (PET) has demonstrated utility for diagnostic and prognostic assessment of cardiac allograft vasculopathy (CAV) but has not been evaluated in the first year after transplant. OBJECTIVES: The authors sought to evaluate CAV at 1 year by PET myocardial blood flow (MBF) quantification. METHODS: Adults at 2 institutions enrolled between January 2018 and March 2021 underwent prospective 3-month (baseline) and 12-month (follow-up) post-transplant PET, endomyocardial biopsy, and intravascular ultrasound examination. Epicardial CAV was assessed by intravascular ultrasound percent intimal volume (PIV) and microvascular CAV by endomyocardial biopsy. RESULTS: A total of 136 PET studies from 74 patients were analyzed. At 12 months, median PIV increased 5.6% (95% CI: 3.6%-7.1%) with no change in microvascular CAV incidence (baseline: 31% vs follow-up: 38%; P = 0.406) and persistent microvascular disease in 13% of patients. Median capillary density increased 30 capillaries/mm2 (95% CI: -6 to 79 capillaries/mm2). PET myocardial flow reserve (2.5 ± 0.7 vs 2.9 ± 0.8; P = 0.001) and stress MBF (2.7 ± 0.6 vs 2.9 ± 0.6; P = 0.008) increased, and coronary vascular resistance (CVR) (49 ± 13 vs 47 ± 11; P = 0.214) was unchanged. At 12 months, PET and PIV had modest correlation (stress MBF: r = -0.35; CVR: r = 0.33), with lower stress MBF and higher CVR across increasing PIV tertiles (all P < 0.05). Receiver-operating characteristic curves for CAV defined by upper-tertile PIV showed areas under the curve of 0.74 for stress MBF and 0.73 for CVR. CONCLUSIONS: The 1-year post-transplant PET MBF is associated with epicardial CAV, supporting potential use for early noninvasive CAV assessment. (Early Post Transplant Cardiac Allograft Vasculopahty [ECAV]; NCT03217786).

Reproducibility of cardiac magnetic resonance imaging in patients referred for the assessment of cardiac sarcoidosis; implications for clinical practice.

Cardiac sarcoidosis (CS) is an increasingly recognized condition, but cardiac magnetic resonance (CMR) image interpretation in these patients may be challenging as findings are often non-specific. The main objective of this study was to investigate the inter-reader agreement for the overall interpretation of CMR for the diagnosis of CS in an experienced reference center and investigate factors that may lead to discrepancies between readers. Consecutive patients undergoing CMR imaging to investigate for CS were included. CMR images were independently reviewed by two readers, blinded to all clinical, imaging and demographic information. The readers classified each scan as "consistent with cardiac sarcoidosis", "not consistent with cardiac sarcoidosis" or "indeterminate". Inter-reader agreement was assessed using κ-statistics. When there was disagreement on the overall interpretation, a third reader reviewed the images. Also, two readers independently commented on the presence of edema, presence of LGE (both ventricles) and quantified the extent of left ventricular LGE. 87 patients (43 women, mean age 54.3 ± 12.2 years) were included in the study. There was agreement regarding the overall interpretation in 72 of 87 (83%) CMR scans. The κ value was 0.64, indicating moderate agreement. There was similar moderate agreement in the interpretation of LGE parameters. In an experienced referral center, we found moderate agreement between readers in the interpretation of CMR in patients with suspected CS. Physicians should be aware of this inter-observer variability in interpretation of CMR studies in patients with suspected CS.

PET Assessment of Epicardial Intimal Disease and Microvascular Dysfunction in Cardiac Allograft Vasculopathy.

BACKGROUND: Cardiac allograft vasculopathy (CAV) is a leading cause of graft failure and death after heart transplantation. Absolute myocardial blood flow (MBF) quantification using rubidium 82 (Rb-82) positron emission tomography (PET) could enable evaluation of diagnostically challenging diffuse epicardial and microvascular disease in CAV. OBJECTIVES: The authors aimed to evaluate Rb-82 PET detection of CAV. METHODS: Consecutive transplant recipients undergoing coronary angiography were prospectively evaluated with PET, multivessel intravascular ultrasound (IVUS), and intracoronary hemodynamics. CAV was defined as International Society of Heart and Lung Transplantation CAV1-3 on angiography and maximal intimal thickness ≥0.5 mm on IVUS. RESULTS: Forty patients (mean age 56 years, 4.8 years post-transplant) completed evaluation. CAV was detected in 32 patients (80%) by IVUS and 14 (35%) by angiography. PET correlated significantly with invasive coronary flow indices: r = 0.29, rate-pressure product-adjusted myocardial flow reserve (cMFR) versus coronary flow reserve; r = 0.28, relative flow reserve versus fractional flow reserve; and r = 0.37, coronary vascular resistance (CVR) versus index of microcirculatory resistance. Patients with CAV or microvascular dysfunction had reduced cMFR and stress MBF and increased CVR. Receiver operator characteristic curves demonstrated good accuracy of PET for CAV on IVUS (area under the curve 0.77 to 0.81) and optimal diagnostic cutoffs of cMFR <2.9, stress MBF <2.3, and CVR >55. Combined PET assessment for CAV yielded excellent >93% sensitivity (>65% specificity) for 1 abnormal parameter and >96% specificity (>55% sensitivity) for 2 abnormal parameters. CONCLUSIONS: Rb-82 PET flow quantification has high diagnostic accuracy for CAV, with potential for noninvasive evaluation after heart transplantation.

Inter- and Intraobserver Agreement of 18F-FDG PET/CT Image Interpretation in Patients Referred for Assessment of Cardiac Sarcoidosis.

Recent studies have reported the usefulness of 18F-FDG PET in aiding with the diagnosis and management of patients with cardiac sarcoidosis (CS). However, image interpretation of 18F-FDG PET for CS is sometimes challenging. We sought to investigate the inter- and intraobserver agreement and explore factors that led to important discrepancies between readers. Methods: We studied consecutive patients with no significant coronary artery disease who were referred for assessment of CS. Two experienced readers masked to clinical information, imaging reports, independently reviewed 18F-FDG PET/CT images. 18F-FDG PET/CT images were interpreted according to a predefined standard operating procedure, with cardiac 18F-FDG uptake patterns categorized into 5 patterns: none, focal, focal on diffuse, diffuse, and isolated lateral wall or basal uptake. Overall image assessment was classified as either consistent with active CS or not. Results: One hundred scans were included from 71 patients. Of these, 46 underwent 18F-FDG PET/CT with a no-restriction diet (no-restriction group), and 54 underwent 18F-FDG PET/CT with a low-carbohydrate, high-fat and protein-permitted diet (low-carb group). There was agreement of the interpretation category in 74 of 100 scans. The κ-value of agreement among all 5 categories was 0.64, indicating moderate agreement. For overall clinical interpretation, there was agreement in 93 of 100 scans (κ = 0.85). When scans were divided into the preparation groups, there was a trend toward higher agreement in the low-carb group versus the no-restriction group (80% vs. 67%, P = 0.08). Regarding the overall clinical interpretation, there was also a trend toward greater agreement in the low-carb group versus the no-restriction group (96% vs. 89%, P = 0.08). Conclusion: The interobserver agreement of cardiac 18F-FDG uptake image patterns was moderate. However, agreement was better regarding overall interpretation of CS. Detailed prescan dietary preparation seemed to improve interobserver agreement.

Validation of a Multimodality Flow Phantom and Its Application for Assessment of Dynamic SPECT and PET Technologies.

Simple and robust techniques are lacking to assess performance of flow quantification using dynamic imaging. We therefore developed a method to qualify flow quantification technologies using a physical compartment exchange phantom and image analysis tool. We validate and demonstrate utility of this method using dynamic PET and SPECT. Dynamic image sequences were acquired on two PET/CT and a cardiac dedicated SPECT (with and without attenuation and scatter corrections) systems. A two-compartment exchange model was fit to image derived time-activity curves to quantify flow rates. Flowmeter measured flow rates (20-300 mL/min) were set prior to imaging and were used as reference truth to which image derived flow rates were compared. Both PET cameras had excellent agreement with truth ( [Formula: see text]). High-end PET had no significant bias (p > 0.05) while lower-end PET had minimal slope bias (wash-in and wash-out slopes were 1.02 and 1.01) but no significant reduction in precision relative to high-end PET (<15% vs. <14% limits of agreement, p > 0.3). SPECT (without scatter and attenuation corrections) slope biases were noted (0.85 and 1.32) and attributed to camera saturation in early time frames. Analysis of wash-out rates from non-saturated, late time frames resulted in excellent agreement with truth ( [Formula: see text], slope = 0.97). Attenuation and scatter corrections did not significantly impact SPECT performance. The proposed phantom, software and quality assurance paradigm can be used to qualify imaging instrumentation and protocols for quantification of kinetic rate parameters using dynamic imaging.

Development of reporter gene imaging techniques for long-term assessment of human circulating angiogenic cells.

The use of biomaterials and tracking the long-term fate of the transplanted cells is expected to help improve the clinical translation of cell therapies for cardiac regeneration. To this end, reporter gene strategies are promising for monitoring the fate of cells transplanted with or without a delivery biomaterial; however, their application with primary adult progenitor cells (such as human circulating angiogenic cells (CACs)) has not been extensively evaluated. In this study, human CACs were transduced with reporter genes via one of two lentiviral (LV) vectors: LV-GFP-iresTK or LV-Fluc-RFP-tTK. The mean transduction efficiency was 15% (LV-GFP-iresTK) and 13% (LV-Fluc-RFP-tTK) at multiplicities of infection (MOI) of 10 and 50, respectively. Western blot analysis confirmed HSV1-tk protein expression in transduced CACs. There was no significant difference in viability between the transduced CACs and the untreated controls at a MOI of 50 or below. However, a reduction was observed in cell viability of CACs transduced with LV-Fluc-RFP-tTK at an MOI of 100. Cell migration and angiogenic potential were not affected by transduction protocol. After 4 weeks, 80.3 ± 8.4% of the labeled cells continued to express the reporters and could be visualized when embedded within a collagen matrix scaffold. Therefore, quiescent human CACs can be stably transduced to express reporter genes without affecting their function. This reporter gene technique is a promising approach to be further tested for tracking transplanted CACs (±delivery matrix) non-invasively and longitudinally.

Clinical interpretation standards and quality assurance for the multicenter PET/CT trial rubidium-ARMI.

UNLABELLED: Rubidium-ARMI ((82)Rb as an Alternative Radiopharmaceutical for Myocardial Imaging) is a multicenter trial to evaluate the accuracy, outcomes, and cost-effectiveness of low-dose (82)Rb perfusion imaging using 3-dimensional (3D) PET/CT technology. Standardized imaging protocols are essential to ensure consistent interpretation. METHODS: Cardiac phantom qualifying scans were obtained at 7 recruiting centers. Low-dose (10 MBq/kg) rest and pharmacologic stress (82)Rb PET scans were obtained in 25 patients at each site. Summed stress scores, summed rest scores, and summed difference scores (SSS, SRS, and SDS [respectively] = SSS-SRS) were evaluated using 17-segment visual interpretation with a discretized color map. All scans were coread at the core lab (University of Ottawa Heart Institute) to assess agreement of scoring, clinical diagnosis, and image quality. Scoring differences greater than 3 underwent a third review to improve consensus. Scoring agreement was evaluated with intraclass correlation coefficient (ICC-r), concordance of clinical interpretation, and image quality using κ coefficient and percentage agreement. Patient (99m)Tc and (201)Tl SPECT scans (n = 25) from 2 centers were analyzed similarly for comparison to (82)Rb. RESULTS: Qualifying scores of SSS = 2, SDS = 2, were achieved uniformly at all imaging sites on 9 different 3D PET/CT scanners. Patient scores showed good agreement between core and recruiting sites: ICC-r = 0.92, 0.77 for SSS, SDS. Eighty-five and eighty-seven percent of SSS and SDS scores, respectively, had site-core differences of 3 or less. After consensus review, scoring agreement improved to ICC-r = 0.97, 0.96 for SSS, SDS (P < 0.05). The agreement of normal versus abnormal (SSS ≥ 4) and nonischemic versus ischemic (SDS ≥ 2) studies was excellent: ICC-r = 0.90 and 0.88. Overall interpretation showed excellent agreement, with a κ = 0.94. Image quality was perceived differently by the site versus core reviewers (90% vs. 76% good or better; P < 0.05). By comparison, scoring agreement of the SPECT scans was ICC-r = 0.82, 0.72 for SSS, SDS. Seventy-six and eighty-eight percent of SSS and SDS scores, respectively, had site-core differences of 3 or less. Consensus review again improved scoring agreement to ICC-r = 0.97, 0.90 for SSS, SDS (P < 0.05). CONCLUSION: (82)Rb myocardial perfusion imaging protocols were implemented with highly repeatable interpretation in centers using 3D PET/CT technology, through an effective standardization and quality assurance program. Site scoring of (82)Rb PET myocardial perfusion imaging scans was found to be in good agreement with core lab standards, suggesting that the data from these centers may be combined for analysis of the rubidium-ARMI endpoints.

Mitochondrial uncoupling in skeletal muscle by UCP1 augments energy expenditure and glutathione content while mitigating ROS production.

Enhancement of proton leaks in muscle tissue represents a potential target for obesity treatment. In this study, we examined the bioenergetic and physiological implications of increased proton leak in skeletal muscle. To induce muscle-specific increases in proton leak, we used mice that selectively express uncoupling protein-1 (UCP1) in skeletal muscle tissue. UCP1 expression in muscle mitochondria was ∼13% of levels in brown adipose tissue (BAT) mitochondria and caused increased GDP-sensitive proton leak. This was associated with an increase in whole body energy expenditure and a decrease in white adipose tissue content. Muscle UCP1 activity had divergent effects on mitochondrial ROS emission and glutathione levels compared with BAT. UCP1 in muscle increased total mitochondrial glutathione levels ∼7.6 fold. Intriguingly, unlike in BAT mitochondria, leak through UCP1 in muscle controlled mitochondrial ROS emission. Inhibition of UCP1 with GDP in muscle mitochondria increased ROS emission ∼2.8-fold relative to WT muscle mitochondria. GDP had no impact on ROS emission from BAT mitochondria from either genotype. Collectively, these findings indicate that selective induction of UCP1-mediated proton leak in muscle can increase whole body energy expenditure and decrease adiposity. Moreover, ectopic UCP1 expression in skeletal muscle can control mitochondrial ROS emission, while it apparently plays no such role in its endogenous tissue, brown fat.

Analysis of [11C]methyl-candesartan kinetics in the rat kidney for the assessment of angiotensin II type 1 receptor density in vivo with PET.

INTRODUCTION: Angiotensin II type 1 (AT(1)) receptors play a key role in the regulation of renal and cardiovascular functions and have been implicated in the pathogenesis of many diseases. The aim of this study was to assess binding of the novel radioligand [(11)C]methyl-candesartan to AT(1) receptors in the rat kidney in vivo with PET. METHODS: Dynamic PET images were acquired for 60 min at baseline, with coinjection of candesartan (5 mg/kg), and after injection of PD123,319 (5 mg/kg). Volumes of distribution (R(C)∙V(T)) were estimated with a two-compartment model, by Logan analysis, and by taking the tissue-to-plasma activity ratio at 50-60 min post-injection. RESULTS: The two-compartment model did not describe the kinetics at baseline adequately and the baseline scans were too short to obtain accurate estimates of R(C)∙V(T) with the Logan approach. Based on the tissue-to-plasma ratios, roughly one-third of V(T) at baseline could be attributed to AT(1) receptor binding. There were no indications of AT(2) receptor binding in the rat kidney. CONCLUSION: It may be possible to detect changes in AT(1) receptor density in the rat kidney in vivo with [(11)C]methyl-candesartan and PET. Imaging AT(1) receptors with PET may provide valuable information on the role of these receptors in the pathogenesis of diseases such as hypertension, diabetic nephropathy, ventricular remodeling, and heart failure.

In vivo assessment of myocardial glucose uptake by positron emission tomography in adults with the PRKAG2 cardiac syndrome.

BACKGROUND: The PRKAG2 cardiac syndrome is an inherited metabolic disease of the heart characterized by excessive myocardial glycogen deposition. The biochemical alterations associated with this condition remain controversial and have not previously been studied in affected humans. METHODS AND RESULTS: Positron emission tomography (PET) imaging was used to quantitatively assess myocardial glucose uptake (MGU) in 6 adult subjects with the PRKAG2 cardiac syndrome and 6 healthy, matched control subjects using the glucose analogue (18)F-Fluoro-2-deoxyglucose (FDG). Studies were performed under a euglycemic hyperinsulinemic clamp to ensure stable blood glucose levels. Rubidium-82 perfusion scans were performed to ensure that myocardial differences in myocardial glucose uptake were not the result of significant myocardial scar. In adult patients with phenotypic expression of disease, the median myocardial glucose uptake of the left ventricle was 0.18 mumol/min/g (interquartile range, 0.14, 0.24), compared with 0.40 mumol/min/g (interquartile range, 0.30 to 0.45) in the control group (P=0.01). The median blood glucose during FDG-PET imaging was 4.72 mmol/L (interquartile range, 4.32 to 4.97) in the PRKAG2 group and 4.38 mmol/L (interquartile range, 3.90, 4.79) in the control group (P=NS). The significant decrease observed in myocardial glucose uptake in affected patients occurred in the absence of significant myocardial scar. CONCLUSIONS: The PRKAG2 cardiac syndrome is associated with a reduction of glucose uptake in adult patients affected with this genetic condition. In this pilot study, (18)F-FDG-PET imaging is a useful tool to assess alterations in myocardial glucose transport in this inherited metabolic disease and provide insight into the biochemical pathophysiology of the diseased state.

Evaluation of outcome and cost-effectiveness using an FDG PET-guided approach to management of patients with coronary disease and severe left ventricular dysfunction (PARR-2): rationale, design, and methods.

Patients with severe ventricular dysfunction and coronary disease have high morbidity and mortality. They may benefit from revascularization but have significant perioperative morbidity and mortality. Positron emission tomography (PET) imaging with F-18-fluorodeoxyglucose (FDG) can detect viable myocardium that may recover from revascularization in such patients. It is unclear whether use of FDG PET in this population improves outcome or is cost-effective. The principal aim of this study is to determine whether FDG PET-guided therapy improves clinical outcome compared to standard care. Secondary objectives are to determine whether FDG PET-guided therapy improves left ventricular (LV) function, improves quality of life, and provides a cost benefit versus standard care. Included in this multicenter randomized controlled trial are patients with coronary artery disease and severe LV dysfunction who are referred for revascularization, heart failure, or cardiac transplantation or in whom FDG PET is potentially useful. Consenting subjects will be randomized to therapy directed by FDG PET or standard care. The primary outcome is the composite cardiovascular endpoint of cardiac death, myocardial infarction, transplantation, or rehospitalization for unstable angina or heart failure. Secondary outcomes include health-related quality of life, costs, mortality, cardiovascular events, and LV function. Assuming two-sided alpha=0.05, power=80%, a sample size of 206 patients per group is required to detect a 15% absolute difference in the primary outcome between PET-directed therapy compared to standard care. Analyses will be conducted on an intention-to-treat basis. To our knowledge, this is the first large trial to evaluate whether FDG PET-directed therapy is effective and provides a cost benefit in patients with severe LV dysfunction. If so, thousands of such patients can be risk-stratified to select who is likely to benefit from revascularization.