A Pilot Study of Neurobiological Mechanisms of Stress and Cardiovascular Risk.

Objective: Coronary heart disease is a leading cause of death and disability. Although psychological stress has been identified as an important potential contributor, mechanisms by which stress increases risk of heart disease and mortality are not fully understood. The purpose of this study was to assess mechanisms by which stress acts through the brain and heart to confer increased CHD risk. Methods: Coronary Heart Disease patients (N=10) underwent cardiac imaging with [Tc-99m] sestamibi single photon emission tomography at rest and during a public speaking mental stress task. Patients returned for a second day and underwent positron emission tomography imaging of the brain, heart, bone marrow, aorta (indicating inflammation) and subcutaneous adipose tissue, after injection of [18F]2-fluoro-2-deoxyglucose for assessment of glucose uptake followed mental stress. Patients with (N=4) and without (N=6) mental stress-induced myocardial ischemia were compared for glucose uptake in brain, heart, adipose tissue and aorta with mental stress. Results: Patients with mental stress-induced ischemia showed a pattern of increased uptake in the heart, medial prefrontal cortex, and adipose tissue with stress. In the heart disease group as a whole, activity increase with stress in the medial prefrontal brain and amygdala correlated with stress-induced increases in spleen (r=0.69, p=0.038; and r=0.69, p=0.04 respectfully). Stress-induced frontal lobe increased uptake correlated with stress-induced aorta uptake (r=0.71, p=0.016). Activity in insula and medial prefrontal cortex was correlated with post-stress activity in bone marrow and adipose tissue. Activity in other brain areas not implicated in stress did not show similar correlations. Increases in medial prefrontal activity with stress correlated with increased cardiac glucose uptake with stress, suggestive of myocardial ischemia (r=0.85, p=0.004). Conclusions: These findings suggest a link between brain response to stress in key areas mediating emotion and peripheral organs involved in inflammation and hematopoietic activity, as well as myocardial ischemia, in Coronary Heart Disease patients.

Determination of [N-13]-ammonia extraction fraction in patients with coronary artery disease by calibration to invasive coronary and fractional flow reserve.

BACKGROUND: This study presents a new extraction fraction (EF) model based on physiological measures of invasive coronary flow reserve (CFR) and fractional flow reserve (FFR) in patients with suspected coronary artery disease (CAD) and normal index microcirculatory resistance (IMR). To ascertain the clinical relevance of the new EFs, flow measurements using the newly patient-determined EFs were compared to flow measurements using traditional animal-determined EFs. METHODS: 39 patients were retrospectively selected that included a total of 91 vascular territories with invasive coronary angiography physiological measures. [N-13]-ammonia dynamic rest/adenosine-stress PET imaging was conducted in all patients and absolute myocardial flow was estimated using four published compartmental models. The extraction fraction during hyperemic flow was iteratively estimated by maximizing the agreement between invasive CFR and FFR with the non-invasive analogs myocardial flow reserve (MFR) and relative flow reserve (RFR) at similar physiological states, respectively. RESULTS: Using the new patient-determined EFs, agreement between CFR vs MFR for Model 1 and 2 was moderate and poor for Model 3 and 4. All models showed moderate agreement for FFR vs RFR. When using published models of animal-determined EFs, agreement between CFR vs MFR remained moderate for Model 1 and 2, and poor for Model 3 and 4. Similarly, all models showed moderate agreement for FFR vs RFR using animal-determined EF values. None of the observed differences were statistically significant. CONCLUSIONS: Flow measurements using extraction fraction correction for [N-13]-ammonia based on calibration to invasive intracoronary angiography physiological measures in patients with CAD were not discordant from those reported in the literature. Either patient-determined or traditional animal-determined EF correction, when used with the appropriate flow model, yields moderate agreement with invasive measurements of coronary flow reserve and fractional flow reserve.

Dynamic cardiac PET motion correction using 3D normalized gradient fields in patients and phantom simulations.

This work expands on the implementation of three-dimensional (3D) normalized gradient fields to correct for whole-body motion and cardiac creep in [N-13]-ammonia patient studies and evaluates its accuracy using a dynamic phantom simulation model. METHODS: A full rigid-body algorithm was developed using 3D normalized gradient fields including a multi-resolution step and sampling off the voxel grid to reduce interpolation artifacts. Optimization was performed using a weighted similarity metric that accounts for opposing gradients between images of blood pool and perfused tissue without the need for segmentation. Forty-three retrospective dynamic [N-13]-ammonia PET/CT rest/adenosine-stress patient studies were motion corrected and the mean motion parameters plotted at each frame time point. Motion correction accuracy was assessed using a comprehensive dynamic XCAT simulation incorporating published physiologic parameters of the heart's trajectory following adenosine infusion as well as corrupted attenuation correction commonly observed in clinical studies. Accuracy of the algorithm was assessed objectively by comparing the errors between isosurfaces and centers of mass of the motion corrected XCAT simulations. RESULTS: In the patient studies, the overall mean cranial-to-caudal translation was 7 mm at stress over the duration of the adenosine infusion. Noninvasive clinical measures of relative flow reserve and myocardial flow reserve were highly correlated with their invasive analogues. Motion correction accuracy assessed with the XCAT simulations showed an error of <1 mm in late perfusion frames that broadened gradually to <3 mm in earlier frames containing blood pool. CONCLUSION: This work demonstrates that patients undergoing [N-13]-ammonia dynamic PET/CT exhibit a large cranial-to-caudal translation related to cardiac creep primarily at stress and to a lesser extent at rest, which can be accurately corrected by optimizing their 3D normalized gradient fields. Our approach provides a solution to the challenging condition where the image intensity and its gradients are opposed without the need for segmentation and remains robust in the presence of PET-CT mismatch.

Quantitative clinical nuclear cardiology, part 2: Evolving/emerging applications.

Quantitative analysis has been applied extensively to image processing and interpretation in nuclear cardiology to improve disease diagnosis and risk stratification. This is Part 2 of a two-part continuing medical education article, which will review the potential clinical role for emerging quantitative analysis tools. The article will describe advanced methods for quantifying dyssynchrony, ventricular function and perfusion, and hybrid imaging analysis. This article discusses evolving methods to measure myocardial blood flow with positron emission tomography and single-photon emission computed tomography. Novel quantitative assessments of myocardial viability, microcalcification and in patients with cardiac sarcoidosis and cardiac amyloidosis will also be described. Lastly, we will review the potential role for artificial intelligence to improve image analysis, disease diagnosis, and risk prediction. The potential clinical role for all these novel techniques will be highlighted as well as methods to optimize their implementation. (J Nucl Cardiol 2020).

Quantitative clinical nuclear cardiology, part 2: Evolving/emerging applications.

Quantitative analysis has been applied extensively to image processing and interpretation in nuclear cardiology to improve disease diagnosis and risk stratification. This is Part 2 of a two-part continuing medical education article, which will review the potential clinical role for emerging quantitative analysis tools. The article will describe advanced methods for quantifying dyssynchrony, ventricular function and perfusion, and hybrid imaging analysis. This article discusses evolving methods to measure myocardial blood flow with positron emission tomography and single-photon emission computed tomography. Novel quantitative assessments of myocardial viability, microcalcification and in patients with cardiac sarcoidosis and cardiac amyloidosis will also be described. Lastly, we will review the potential role for artificial intelligence to improve image analysis, disease diagnosis, and risk prediction. The potential clinical role for all these novel techniques will be highlighted as well as methods to optimize their implementation.

Higher Activation of the Rostromedial Prefrontal Cortex During Mental Stress Predicts Major Cardiovascular Disease Events in Individuals With Coronary Artery Disease.

BACKGROUND: Psychological stress is a risk factor for major adverse cardiovascular events (MACE) in individuals with coronary artery disease. Certain brain regions that control both emotional states and cardiac physiology may be involved in this relationship. The rostromedial prefrontal cortex (rmPFC) is an important brain region that processes stress and regulates immune and autonomic functions. Changes in rmPFC activity with emotional stress (reactivity) may be informative of future risk for MACE. METHODS: Participants with stable coronary artery disease underwent acute mental stress testing using a series of standardized speech/arithmetic stressors and simultaneous brain imaging with high-resolution positron emission tomography brain imaging. We defined high rmPFC activation as a difference between stress and control scans greater than the median value for the entire cohort. Interleukin-6 levels 90 minutes after stress, and high-frequency heart rate variability during stress were also assessed. We defined MACE as a composite of cardiovascular death, myocardial infarction, unstable angina with revascularization, and heart failure hospitalization. RESULTS: We studied 148 subjects (69% male) with mean±SD age of 62±8 years. After adjustment for baseline demographics, risk factors, and baseline levels of interleukin-6 and high-frequency heart rate variability, higher rmPFC stress reactivity was independently associated with higher interleukin-6 and lower high-frequency heart rate variability with stress. During a median follow-up of 3 years, 34 subjects (21.3%) experienced a MACE. Each increase of 1 SD in rmPFC activation with mental stress was associated with a 21% increase risk of MACE (hazard ratio, 1.21 [95% CI, 1.08-1.37]). Stress-induced interleukin-6 and high-frequency heart rate variability explained 15.5% and 32.5% of the relationship between rmPFC reactivity and MACE, respectively. Addition of rmPFC reactivity to conventional risk factors improved risk reclassification for MACE prediction, and C-statistic improved from 0.71 to 0.76 (P=0.03). CONCLUSIONS: Greater rmPFC stress reactivity is associated with incident MACE. Immune and autonomic responses to mental stress may play a contributory role.

Rationale and design of the quantification of myocardial blood flow using dynamic PET/CTA-fused imagery (DEMYSTIFY) to determine physiological significance of specific coronary lesions.

BACKGROUND: Coronary physiology assessments have been shown by multiple trials to add clinical value in detecting significant coronary artery disease and predicting cardiovascular outcomes. Fractional flow reserve (FFR) obtained during invasive coronary angiography (ICA) has become the new reference standard for hemodynamic significance detection. Absolute myocardial blood flow (MBF) quantification by means of dynamic positron emission tomography (dPET) has high diagnostic and prognostic values. FFR is an invasive measure and as such cannot be applied broadly, while MBF quantification is commonly performed on standard vascular territories intermixing normal flow from normal regions with abnormal flow from abnormal regions and consequently limiting its diagnostic power. OBJECTIVE: The aim of this study is to provide physicians with reliable software tools for the non-invasive assessment of lesion-specific physiological significance for the entire coronary tree by combining PET-derived absolute flow data and coronary computed tomography angiography (CTA)-derived anatomy and coronary centerlines. METHODS: The dynamic PET/CTA myocardial blood flow assessment with fused imagery (DEMYSTIFY) study is an observational prospective clinical study to develop algorithms and software tools to fuse coronary anatomy data obtained from CTA with dPET data to non-invasively measure absolute MBF, myocardial flow reserve, and relative flow reserve across specific coronary lesions. Patients (N = 108) will be collected from 4 institutions (Emory University Hospital, USA; Chonnam National University Hospital, South Korea; Samsung Medical Center, South Korea; Seoul National University Hospital, South Korea). These results will be compared to those obtained invasively in the catheterization laboratory and to a relatively novel non-invasive technique to estimate FFR based on CTA and computational fluid dynamics. CONCLUSIONS: Success of these developments should lead to the following benefits: (1) eliminate unnecessary invasive coronary angiography in patients with no significant lesions, (2) avoid stenting physiologically insignificant lesions, (3) guide percutaneous coronary interventions process to the location of significant lesions, (4) provide a flow-color-coded 3D roadmap of the entire coronary tree to guide bypass surgery, and (5) use less radiation and lower the cost from unnecessary procedures. TRIAL REGISTRY: The DEMYSTIFY study has been registered on ClinicalTrials.gov with registration number NCT04221594.

Myocardial perfusion imaging: Lessons learned and work to be done-update.

As the second term of our commitment to Journal begins, we, the editors, would like to reflect on a few topics that have relevance today. These include prognostication and paradigm shifts; Serial testing: How to handle data? Is the change in perfusion predictive of outcome and which one? Ischemia-guided therapy: fractional flow reserve vs perfusion vs myocardial blood flow; positron emission tomography (PET) imaging using Rubidium-82 vs N-13 ammonia vs F-18 Flurpiridaz; How to differentiate microvascular disease from 3-vessel disease by PET? The imaging scene outside the United States, what are the differences and similarities? Radiation exposure; Special issues with the new cameras? Is attenuation correction needed? Are there normal databases and are these specific to each camera system? And finally, hybrid imaging with single-photon emission tomography or PET combined with computed tomography angiography or coronary calcium score. We hope these topics are of interest to our readers.

Nuclear Image-Guided Approaches for Cardiac Resynchronization Therapy (CRT).

Cardiac resynchronization therapy (CRT) is a standard treatment for patients with heart failure. However, 30-40 % of the patients having CRT do not respond to CRT with improved clinical symptom and cardiac functions. It is important for CRT response that left ventricular (LV) lead is placed away from scar and at or near the site of the latest mechanical activation. Nuclear image-guided approaches for CRT have shown significant clinical value to assess LV myocardial viability and mechanical dyssynchrony, recommend the optimal LV lead position, and navigate the LV lead to the target coronary venous site. All these techniques, once validated and implemented, should impact the current clinical practice.

3D fusion of LV venous anatomy on fluoroscopy venograms with epicardial surface on SPECT myocardial perfusion images for guiding CRT LV lead placement.

OBJECTIVES: The aim of this study was to develop a 3-dimensional (3D) fusion tool kit to integrate left ventricular (LV) venous anatomy on fluoroscopy venograms with LV epicardial surface on single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) for guiding cardiac resynchronization therapy (CRT) LV lead placement. BACKGROUND: LV lead position is important for CRT response. For LV lead placement into viable regions with late activation, it is important to visualize both LV venous anatomy and myocardium. METHODS: Major LV veins were manually identified on fluoroscopic venograms and automatically reconstructed into a 3D anatomy. 3D LV epicardial surface was extracted from SPECT MPI. SPECT-vein fusion that consisted of geometric alignment, landmark-based registration, and vessel-surface overlay was developed to fuse the 3D venous anatomy with the epicardial surface. The accuracy of this tool was evaluated using computed tomography (CT) venograms. LV epicardial surfaces and veins were manually identified on the CT images and registered with the SPECT image by an independent operator. The locations of the fluoroscopic and CT veins on the SPECT epicardial surfaces were compared using absolute distances on SPECT short-axis slice and the 17-segment model. RESULTS: Ten CRT patients were enrolled. The distance between the corresponding fluoroscopic and CT veins on the short-axis epicardial surfaces was 4.6 ± 3.6 mm (range 0 to 16.9 mm). The presence of the corresponding fluoroscopic and CT veins in the 17-segment model agreed well with a kappa value of 0.87 (95% confidence interval: 0.82 to 0.93). The tool kit was used to guide LV lead placement in a catheter laboratory and showed clinical feasibility and benefit to the patient. CONCLUSIONS: A tool kit has been developed to reconstruct 3D LV venous anatomy from dual-view fluoroscopic venograms and to fuse it with LV epicardial surface on SPECT MPI. It is technically accurate for guiding LV lead placement by the 17-segment model and is feasible for clinical use in the catheterization laboratory.

Patient-centered imaging: shared decision making for cardiac imaging procedures with exposure to ionizing radiation.

The current paper details the recommendations arising from an NIH-NHLBI/NCI-sponsored symposium held in November 2012, aiming to identify key components of a radiation accountability framework fostering patient-centered imaging and shared decision-making in cardiac imaging. Symposium participants, working in 3 tracks, identified key components of a framework to target critical radiation safety issues for the patient, the laboratory, and the larger population of patients with known or suspected cardiovascular disease. The use of ionizing radiation during an imaging procedure should be disclosed to all patients by the ordering provider at the time of ordering, and reinforced by the performing provider team. An imaging protocol with effective dose ≤3 mSv is considered very low risk, not warranting extensive discussion or written informed consent. However, a protocol effective dose >20 mSv was proposed as a level requiring particular attention in terms of shared decision-making and either formal discussion or written informed consent. Laboratory reporting of radiation dosimetry is a critical component of creating a quality laboratory fostering a patient-centered environment with transparent procedural methodology. Efforts should be directed to avoiding testing involving radiation, in patients with inappropriate indications. Standardized reporting and diagnostic reference levels for computed tomography and nuclear cardiology are important for the goal of public reporting of laboratory radiation dose levels in conjunction with diagnostic performance. The development of cardiac imaging technologies revolutionized cardiology practice by allowing routine, noninvasive assessment of myocardial perfusion and anatomy. It is now incumbent upon the imaging community to create an accountability framework to safely drive appropriate imaging utilization.

Prompt-gamma compensation in Rb-82 myocardial perfusion 3D PET/CT.

OBJECTIVE: To compare the diagnostic accuracy of Rb-82 myocardial perfusion three-dimensional (3D) PET with and without prompt-gamma compensation (PGC). METHODS AND RESULTS: Retrospective, single center study of 76 patients who had rest and adenosine stress Rb-82 myocardial perfusion 3D PET. All studies were acquired using a Siemens Biograph-40 PET/CT scanner and were reconstructed with and without PGC. Fifty-seven patients (mean age 63 +/- 11 years, 26 men) had coronary angiography within 40 days of Rb-82 imaging. Nineteen patients (mean age 43 +/- 7 years, 10 men) had low likelihood of coronary artery disease (CAD). All PET images were scored by consensus of two blinded readers on a standard 5-point scale using a 17-segment left ventricular model. A normal PET test was defined as a summed stress score of less than four. Obstructive CAD at coronary angiography was used as the gold-standard and was defined as luminal stenoses > or =50% in one or more major coronary arteries. The prevalence of obstructive disease at coronary angiography was 68% (39/57). The mean summed stress score was 12 +/- 12 for PGC images and was 18 +/- 14 for non-PGC images. Sensitivity and specificity for obstructive CAD were 90% (95% CI 88-99) and 72% (95% CI 52-93) for PGC images and 95% (95% CI 88-100) and 22% (95% CI 3-41) for non-PGC images. CONCLUSION: PGC in Rb-82 3D PET improves the specificity for obstructive CAD at coronary angiography with no significant loss in sensitivity.

Investigation of emission-transmission misalignment artifacts on rubidium-82 cardiac PET with adenosine pharmacologic stress.

PURPOSE: This study was undertaken to determine if artifacts from misalignment of cardiac emission to transmission data is present in adenosine stress studies and if the artifact could be reproduced by intentional misalignment in normal exams. PROCEDURES: Seventy consecutive 82Rb myocardial perfusion studies were reviewed. Utilizing a quality control program, misalignment was assessed. The study was reprocessed after manual realignment to determine if the defect extent changed. Emission and transmission acquisitions in six normal studies also were intentionally misaligned. RESULTS: Twenty of 69 rest studies (29.0%) and 17 of 69 (24.6%) stress studies demonstrated misalignment. In four patients with stress misalignment, there was a significant change in clinical interpretation. Upon intentionally misaligning six normal studies, a lateral wall defect was reproduced. CONCLUSIONS: Emission-transmission misalignment occurs in 29.0% and 24.6% of 82Rb rest and adenosine stress studies, respectively. While there is a positive correlation of artifactual defects with misalignment, the presence and size of artifacts is variable and unpredictable at seemingly lesser degrees of misalignment.

Quantitative (82)Rb PET/CT: development and validation of myocardial perfusion database.

UNLABELLED: The use of myocardial perfusion (82)Rb PET/CT studies continues to increase but its accuracy using database quantification methods for the diagnosis of coronary artery disease (CAD) has not been established. METHODS: A sex-independent normal database and criteria for abnormality for rest-stress (82)Rb PET/CT myocardial perfusion imaging were developed and validated by evaluation of 281 patients (136 females: mean age +/- SD, 63.3 +/- 13.3 y; 145 males: mean age +/- SD, 63.9 +/- 12.8 y) who underwent a rest-adenosine stress (82)Rb PET/CT study. These patients were divided into 3 groups: (a) healthy group: 30 patients, with <5% likelihood of CAD (low likelihood [LLK]) based on sequential Bayesian analysis; these patients were used to generate the normal distribution; (b) pilot group: 174 patients; these patients were used to determine the optimal criteria for detecting and localizing the perfusion abnormality; and (c) validation group: 76 patients (23 with LLK of CAD and 53 who underwent coronary angiography; these patients were used for prospective validation. RESULTS: Of the 53 patients who underwent coronary angiography, 8 had <50% stenosis and 45 patients had at least one stenosis > or =50% in one major artery. Fifteen patients had single-vessel disease, 17 had double-vessel disease, and 13 had triple-vessel disease. The prospective validation shows a normalcy rate of 78% (18/23) for global CAD. The analyses by individual arteries show a normalcy rate of 96% (22/23) for the left anterior descending coronary artery, 96% for the left circumflex coronary artery (22/23), and 100% for the right coronary artery (23/23). The overall sensitivity for detection of CAD (> or =50% stenosis) was 93% (42/45). The overall specificity for detection of the absence of CAD (< or =50% stenosis) was 75% (6/8). Also, the positive predictive value for global CAD was 95% (42/44), the negative predictive value was 67% (6/9), and the accuracy was 91% (48/53). CONCLUSION: The quantitative (82)Rb PET/CT database created and validated in this study is highly accurate for the detection and localization of CAD. Physicians should consider using the quantitative output of these algorithms as decision support tools to aid with image interpretation.

Feasibility of detecting cardiac torsion in myocardial perfusion gated SPECT data.

BACKGROUND: The dynamic twisting component of cardiac motion is not accounted for by radionuclide techniques so that maps of perfusion and wall thickening are motion-blurred by torsion. This study examined whether torsion can be estimated from gated single photon emission computed tomography data and whether torsion corrections affect cardiac measurements. METHODS AND RESULTS: Technetium 99m sestamibi myocardial perfusion gated tomograms were selected retrospectively for 52 patients who had x-ray contrast arteriograms: 12 with normal perfusion (group 1), 12 with abnormal perfusion (group 2), and 28 studied after angioplasty (group 3). The 8 gated perfusion maps were transformed by contrast normalization, the count minimums of which were tracked to quantify torsion. Measured torsion was used to correct maps of perfusion and wall thickening. Torsion was found to be visually detectable equally well in groups 1 and 2. Apical torsion was significantly greater for group 1 than groups 2 and 3 (15 degrees +/- 9 degrees vs 9 degrees +/- 15 degrees and 2 degrees +/- 12 degrees ) and was opposite in sign for patients with apical aneurysms (-4 degrees +/- 13 degrees ) and for patients after coronary artery bypass grafting (CABG) (-4 degrees +/- 15 degrees ). Maximum percent count differences were 10% +/- 16% between torsion-corrected versus uncorrected perfusion maps. The greatest wall thickening differences were seen for patients with left ventricular apical aneurysms and for patients after CABG versus group 1 (10% +/- 6% and 8% +/- 6% vs 3% +/- 1%, respectively). CONCLUSIONS: It is feasible to detect cardiac torsion in the majority of Tc-99m sestamibi myocardial perfusion scans. Abnormal twisting patterns distinguished patients after CABG and those with left ventricular aneurysms from subjects with normal perfusion in a manner similar to magnetic resonance imaging observations.