Inflammation and Myocardial Blood Flow in Cardiac Sarcoidosis.

PURPOSE OF THE REVIEW: Cardiac involvement in systemic sarcoidosis or isolated cardiac sarcoidosis plays a pivotal role in the clinical manifestation and prognostication. Active-inflammatory cardiac sarcoidosis is associated with a regional impairment of coronary microvascular function that may confer further detrimental effects on myocardial function needing further characterization. RECENT FINDINGS: Clinical investigations with cardiac positron emission tomography/computed tomography in conjunction with 18F-fluorodeoxyglucose to determine myocardial inflammation and 13N-ammonia to quantify myocardial blood flow (MBF) in patients with known or suspected cardiac sarcoidosis outlined that sarcoidosis-induced myocardial inflammation was associated with adverse effects on corresponding regional coronary microvascular function. Notably, immune-suppressive treatment caused reductions in myocardial inflammation were paralleled by improvements of coronary microvascular dysfunction outlining direct adverse effect of inflammation on coronary arteriolar function. This review summarizes contributions of cardiac PET imaging in the identification and characterization of active-inflammatory cardiac sarcoidosis, its effect on coronary microvascular function, treatment responses, and prognostic implications.

Total-Body PET/CT Applications in Cardiovascular Diseases: A Perspective Document of the SNMMI Cardiovascular Council.

Digital PET/CT systems with a long axial field of view have become available and are emerging as the current state of the art. These new camera systems provide wider anatomic coverage, leading to major increases in system sensitivity. Preliminary results have demonstrated improvements in image quality and quantification, as well as substantial advantages in tracer kinetic modeling from dynamic imaging. These systems also potentially allow for low-dose examinations and major reductions in acquisition time. Thereby, they hold great promise to improve PET-based interrogation of cardiac physiology and biology. Additionally, the whole-body coverage enables simultaneous assessment of multiple organs and the large vascular structures of the body, opening new opportunities for imaging systemic mechanisms, disorders, or treatments and their interactions with the cardiovascular system as a whole. The aim of this perspective document is to debate the potential applications, challenges, opportunities, and remaining challenges of applying PET/CT with a long axial field of view to the field of cardiovascular disease.

PET-determined myocardial perfusion and flow in coronary artery disease characterization.

Positron emission tomography (PET) myocardial perfusion imaging in conjunction with tracer-kinetic modeling enables the concurrent assessment of myocardial perfusion and regional myocardial blood flow (MBF) of the left ventricle in absolute terms in milliliters per gram per minute (mL/g/min). The non-invasive quantification of MBF during pharmacologically induced hyperemia, at rest, and corresponding myocardial flow reserve (MFR) opens a new avenue for the identification and characterization of classical or endogen type of coronary microvascular dysfunction (CMD) as functional substrate for microvascular angina in patients with non-obstructive coronary artery disease (CAD) and/or no CAD at all. Further, PET-MBF quantification expands the scope of conventional myocardial perfusion imaging from the identification of advanced, and flow-limiting, epicardial CAD to early stages of atherosclerosis and/or CMD. Adding MBF assessment to myocardial perfusion may also reliably unravel diffuse ischemia owing to significant left main stenosis and/or multivessel CAD, commonly confirmed by peak stress transient ischemic cavity dilation of the left ventricle during maximal vasomotor stress compared to rest on gated PET images. Owing to high spatial and contrast resolution in conjunction with photon-attenuation free myocardial perfusion PET images, PET is preferentially used for CAD detection in advanced obesity and women with pronounced breast habitus. With increasing clinical use of cardiac PET perfusion and MBF assessment, individualized, and image-guided cardiovascular treatment decisions in CAD patients is likely to ensue, while its translation into improved cardiovascular outcome remains to be investigated.

Early diagnosis and management of cardiac amyloidosis: A clinical perspective.

Cardiac amyloidosis multidisciplinary team (MDT). We propose the creation of a multidisciplinary team (MDT) for cardiac amyloidosis in which internal medicine physicians could take a lead role in coordinating other specialists involved in patient care. Created with BioRender.com.

Systolic blood pressure ≤110 mm Hg is associated with severe coronary microvascular ischemia and higher risk for ventricular arrhythmias in hypertrophic cardiomyopathy.

Background: Coronary microvascular dysfunction (CMD) and hypertension (HTN) occur frequently in hypertrophic cardiomyopathy (HCM), but whether blood pressure (BP) influences CMD and outcomes is unknown. Objective: The purpose of this study was to test the hypothesis that HTN is associated with worse CMD and outcomes. Methods: This retrospective study included 690 HCM patients. All patients underwent cardiac magnetic resonance imaging, echocardiography, and rhythm monitoring; 127 patients also underwent rest/vasodilator stress 13NH3 positron emission tomography myocardial perfusion imaging. Patients were divided into 3 groups based on their rest systolic blood pressure (SBP) (group 1 ≤110 mm Hg; group 2 111-140; group 3 >140 mm Hg) and were followed for development of ventricular tachycardia (VT)/ventricular fibrillation (VF), heart failure (HF), death, and composite outcome. Results: Group 1 patients had the lowest age and left ventricular (LV) mass but the highest prevalence of nonobstructive hemodynamics and restrictive diastolic filling. LV scar was similar in the 3 groups. Group 1 had the lowest rest and stress myocardial blood flow (MBF) and highest SDS (summed difference score). Rest SBP was positively correlated with stress MBF and negatively correlated with SDS. Group 1 had the highest incidence of VT/VF, whereas the incidences of HF, death, and composite outcome were similar among the 3 groups. In multivariate analysis, rest SBP ≤110 mm Hg was independently associated with VT/VF (hazard ratio 2.6; 95% confidence interval 1.0-6.7; P = .04). Conclusion: SBP ≤110 mm Hg is associated with greater severity of CMD and coronary microvascular ischemia and higher incidence of ventricular arrhythmias in HCM.

Standardized Radiomics Analysis of Clinical Myocardial Perfusion Stress SPECT Images to Identify Coronary Artery Calcification.

PURPOSE: Myocardial perfusion (MP) stress single-photon emission computed tomography (SPECT) is an established diagnostic test for patients suspected of coronary artery disease (CAD). Meanwhile, coronary artery calcification (CAC) scoring obtained from diagnostic CT is a highly sensitive test, offering incremental diagnostic information in identifying patients with significant CAD yet normal MP stress SPECT (MPSS) scans. However, after decades of wide utilization of MPSS, CAC is not commonly reimbursed (e.g. by the CMS), nor widely deployed in community settings. We studied the potential of complementary information deduced from the radiomics analysis of normal MPSS scans in predicting the CAC score. METHODS: We collected data from 428 patients with normal (non-ischemic) MPSS (99mTc-sestamibi; consensus reading). A nuclear medicine physician verified iteratively reconstructed images (attenuation-corrected) to be free from fixed perfusion defects and artifactual attenuation. Three-dimensional images were automatically segmented into four regions of interest (ROIs), including myocardium and three vascular segments (left anterior descending [LAD]-left circumference [LCX]-right coronary artery [RCA]). We used our software package, standardized environment for radiomics analysis (SERA), to extract 487 radiomic features in compliance with the image biomarker standardization initiative (IBSI). Isotropic cubic voxels were discretized using fixed bin-number discretization (eight schemes). We first performed blind-to-outcome feature selection focusing on a priori usefulness, dynamic range, and redundancy of features. Subsequently, we performed univariate and multivariate machine learning analyses to predict CAC scores from i) selected radiomic features, ii) 10 clinical features, and iii) combined radiomics + clinical features. Univariate analysis invoked Spearman correlation with Benjamini-Hotchberg false-discovery correction. The multivariate analysis incorporated stepwise linear regression, where we randomly selected a 15% test set and divided the other 85% of data into 70% training and 30% validation sets. Training started from a constant (intercept) model, iteratively adding/removing features (stepwise regression), invoking the Akaike information criterion (AIC) to discourage overfitting. Validation was run similarly, except that the training output model was used as the initial model. We randomized training/validation sets 20 times, selecting the best model using log-likelihood for evaluation in the test set. Assessment in the test set was performed thoroughly by running the entire operation 50 times, subsequently employing Fisher's method to verify the significance of independent tests. RESULTS: Unsupervised feature selection significantly reduced 8×487 features to 56. In univariate analysis, no feature survived the false-discovery rate (FDR) to directly correlate with CAC scores. Applying Fisher's method to the multivariate regression results demonstrated combining radiomics with the clinical features to enhance the significance of the prediction model across all cardiac segments.  Conclusions: Our standardized and statistically robust multivariate analysis demonstrated significant prediction of the CAC score for all cardiac segments when combining MPSS radiomic features with clinical features, suggesting radiomics analysis can add diagnostic or prognostic value to standard MPSS for wide clinical usage.

Oxaliplatin-induced cardiotoxicity in mice is connected to the changes in energy metabolism in the heart tissue.

Oxaliplatin is a platinum-based alkylating chemotherapeutic agent used for cancer treatment. At high cumulative dosage, the negative effect of oxaliplatin on the heart becomes evident and is linked to a growing number of clinical reports. The aim of this study was to determine how chronic oxaliplatin treatment causes the changes in energy-related metabolic activity in the heart that leads to cardiotoxicity and heart damage in mice. C57BL/6 male mice were treated with a human equivalent dosage of intraperitoneal oxaliplatin (0 and 10 mg/kg) once a week for eight weeks. During the treatment, mice were followed for physiological parameters, ECG, histology and RNA sequencing of the heart. We identified that oxaliplatin induces strong changes in the heart and affects the heart's energy-related metabolic profile. Histological post-mortem evaluation identified focal myocardial necrosis infiltrated with a small number of associated neutrophils. Accumulated doses of oxaliplatin led to significant changes in gene expression related to energy related metabolic pathways including fatty acid (FA) oxidation, amino acid metabolism, glycolysis, electron transport chain, and NAD synthesis pathway. At high accumulative doses of oxaliplatin, the heart shifts its metabolism from FAs to glycolysis and increases lactate production. It also leads to strong overexpression of genes in NAD synthesis pathways such as Nmrk2. Changes in gene expression associated with energy metabolic pathways can be used to develop diagnostic methods to detect oxaliplatin-induced cardiotoxicity early on as well as therapy to compensate for the energy deficit in the heart to prevent heart damage.

Novel Diagnostic Imaging Approach for Patients With Spontaneous Coronary Artery Dissection: The Utility of 18 F-FDG PET Imaging.

ABSTRACT: Spontaneous coronary artery dissection (SCAD) is an underdiagnosed etiology of acute coronary syndrome in women. Accurate diagnosis remains challenging but is imperative for treatment and prevention. We show here the utility of 18 F-FDG PET imaging in SCAD diagnosis. We present 1 representative case of 4 women with suspected SCAD on coronary angiography from the EVACS (Evolocumab in Acute Coronary Syndromes) clinical trial. 18 F-FDG PET imaging showed acute inflammation in the distribution of the suspected dissected coronary artery identified on angiography. Localized myocardial inflammation identified on 18 F-FDG PET imaging can aid in diagnosing SCAD suspected on coronary angiography.

Emerging role of PET/MR in the diagnosis and characterization of cardiotoxicity?

In cardiotoxicity, PET/MR affords an accurate evaluation of cardiovascular morphology, function, and also multi-parametric tissue characterization. A composite of several cardiac imaging parameters provided by the PET/MR scanner is likely to outperform a single parameter or imaging modality in the assessment and prediction of the severity and progression of cardiotoxicity but needing clinical investigations. Of particular interest, a heterogeneity map of single PET and CMR parameters could be perfectly correlated with the PET/MR scanner likely emerging as a promising marker of cardiotoxicity to monitor treatment response. While such functional and structural multiparametric imaging approach with cardiac PET/MR in the assessment and characterization of cardiotoxicity holds much promise, its validity and value in cancer patients treated with chemotherapy and/or radiation still needs to be assessed. The multi-parametric imaging approach with PET/MR, however, is likely to set new standards to develop predictive constellations of parameters for the severity and potential progression of cardiotoxicity that should afford timely and individualized treatment intervention to ascertain myocardial recovery and improved clinical outcome in these high-risk patients.

Need for objective task-based evaluation of deep learning-based denoising methods: A study in the context of myocardial perfusion SPECT.

BACKGROUND: Artificial intelligence-based methods have generated substantial interest in nuclear medicine. An area of significant interest has been the use of deep-learning (DL)-based approaches for denoising images acquired with lower doses, shorter acquisition times, or both. Objective evaluation of these approaches is essential for clinical application. PURPOSE: DL-based approaches for denoising nuclear-medicine images have typically been evaluated using fidelity-based figures of merit (FoMs) such as root mean squared error (RMSE) and structural similarity index measure (SSIM). However, these images are acquired for clinical tasks and thus should be evaluated based on their performance in these tasks. Our objectives were to: (1) investigate whether evaluation with these FoMs is consistent with objective clinical-task-based evaluation; (2) provide a theoretical analysis for determining the impact of denoising on signal-detection tasks; and (3) demonstrate the utility of virtual imaging trials (VITs) to evaluate DL-based methods. METHODS: A VIT to evaluate a DL-based method for denoising myocardial perfusion SPECT (MPS) images was conducted. To conduct this evaluation study, we followed the recently published best practices for the evaluation of AI algorithms for nuclear medicine (the RELAINCE guidelines). An anthropomorphic patient population modeling clinically relevant variability was simulated. Projection data for this patient population at normal and low-dose count levels (20%, 15%, 10%, 5%) were generated using well-validated Monte Carlo-based simulations. The images were reconstructed using a 3-D ordered-subsets expectation maximization-based approach. Next, the low-dose images were denoised using a commonly used convolutional neural network-based approach. The impact of DL-based denoising was evaluated using both fidelity-based FoMs and area under the receiver operating characteristic curve (AUC), which quantified performance on the clinical task of detecting perfusion defects in MPS images as obtained using a model observer with anthropomorphic channels. We then provide a mathematical treatment to probe the impact of post-processing operations on signal-detection tasks and use this treatment to analyze the findings of this study. RESULTS: Based on fidelity-based FoMs, denoising using the considered DL-based method led to significantly superior performance. However, based on ROC analysis, denoising did not improve, and in fact, often degraded detection-task performance. This discordance between fidelity-based FoMs and task-based evaluation was observed at all the low-dose levels and for different cardiac-defect types. Our theoretical analysis revealed that the major reason for this degraded performance was that the denoising method reduced the difference in the means of the reconstructed images and of the channel operator-extracted feature vectors between the defect-absent and defect-present cases. CONCLUSIONS: The results show the discrepancy between the evaluation of DL-based methods with fidelity-based metrics versus the evaluation on clinical tasks. This motivates the need for objective task-based evaluation of DL-based denoising approaches. Further, this study shows how VITs provide a mechanism to conduct such evaluations computationally, in a time and resource-efficient setting, and avoid risks such as radiation dose to the patient. Finally, our theoretical treatment reveals insights into the reasons for the limited performance of the denoising approach and may be used to probe the effect of other post-processing operations on signal-detection tasks.

PET-determined prevalence of coronary microvascular dysfunction and different types in a cardio-metabolic risk population.

Background: The aim was to investigate the prevalence of "classical" (predominantly related to alterations in hyperemic MBFs) and "endogen" (predominantly related to alterations in resting MBF) normal coronary microvascular function (nCMF) or coronary microvascular dysfunction (CMD) in a clinical population without flow-limiting obstructive CAD. Methods: We prospectively enrolled 239 symptomatic patients with normal pharmacologically-stress and rest myocardial perfusion on 13N-ammonia PET/CT. 13N-ammonia PET/CT concurrently assessed myocardial flow reserve (MFR = MBF stress/MBF rest). Normal nCMF was defined by a MFR of ≥ 2.0, while an abnormal MFR of < 2.0 signified CMD. In addition, patients were subgrouped into classical and endogen type of nCMF and CMD, respectively. Results: In the whole study population, CMD was present in 54% (130/239). The classical type was more prevalent than the endogen type of CMD (65% vs 35%, p ≤ 0.008). The classical type of CMD was paralleled by a high prevalence of diabetes mellitus, metabolic syndrome, and obesity, while the endogen type of CMD was accompanied by a higher prevalence of arterial hypertension, obesity, and/or morbid obesity. Further, the classical type of nCMF was more frequently observed that the endogen type (74% vs. 26%, p ≤ 0.007). The endogen type of nCMF was related to lower heart rate and/or arterial blood pressures. Conclusions: In this contemporary clinical study population, slightly more than half of symptomatic patients had CMD with predominance of the classical type. These observations emphasize the need for standardized reporting of CMD to gear individualized and/or intensified medical treatment to improve symptoms and/or clinical outcome in these patients.

Myocardial Perfusion PET for the Detection and Reporting of Coronary Microvascular Dysfunction: A JACC: Cardiovascular Imaging Expert Panel Statement.

Angina pectoris and dyspnea in patients with normal or nonobstructive coronary vessels remains a diagnostic challenge. Invasive coronary angiography may identify up to 60% of patients with nonobstructive coronary artery disease (CAD), of whom nearly two-thirds may, in fact, have coronary microvascular dysfunction (CMD) that may account for their symptoms. Positron emission tomography (PET) determined absolute quantitative myocardial blood flow (MBF) at rest and during hyperemic vasodilation with subsequent derivation of myocardial flow reserve (MFR) affords the noninvasive detection and delineation of CMD. Individualized or intensified medical therapies with nitrates, calcium-channel blockers, statins, angiotensin-converting enzyme inhibitors, angiotensin II type 1-receptor blockers, beta-blockers, ivabradine, or ranolazine may improve symptoms, quality of life, and outcome in these patients. Standardized diagnosis and reporting criteria for ischemic symptoms caused by CMD are critical for optimized and individualized treatment decisions in such patients. In this respect, it was proposed by the cardiovascular council leadership of the Society of Nuclear Medicine and Molecular Imaging to convene thoughtful leaders from around the world to serve as an independent expert panel to develop standardized diagnosis, nomenclature and nosology, and cardiac PET reporting criteria for CMD. This consensus document aims to provide an overview of the pathophysiology and clinical evidence of CMD, its invasive and noninvasive assessment, standardization of PET-determined MBFs and MFR into "classical" (predominantly related to hyperemic MBFs) and "endogen" (predominantly related to resting MBF) normal coronary microvascular function or CMD that may be critical for diagnosis of microvascular angina, subsequent patient care, and outcome of clinical CMD trials.