Al[18F]F-complexation of DFH17, a NOTA-conjugated adrenomedullin analog, for PET imaging of pulmonary circulation.

INTRODUCTION: Adrenomedullin receptors are highly expressed in human alveolar capillaries and provide a molecular target for imaging the integrity of pulmonary microcirculation. In this work, we aimed to develop a NOTA-derivatized adrenomedullin analog (DFH17), radiolabeled with [18F]AlF, for PET imaging of pulmonary microcirculation. METHODS: Highly concentrated [18F](AlF)2+ (15 µL) was produced from purified fluorine-18 in NaCl 0.9%. Various complexation experiments were carried out at Al-to-NOTA molar ratios ranging from 1:1 to 1:40 to assess optimal radiolabeling conditions before using the peptide. DFH17 peptide (2 mM, pH 4) was radiolabeled with [18F](AlF)2+ for 15 min at 100 °C in a total volume of 60 µL. As part of the radiolabeling process, parameters such as fluorine-18 activity (~37 and 1480 MBq), concentration of AlCl3 (0.75, 2, 3, 6 or 10 mM) and the effects of hydrophilic organic solvent (aqueous vs ethanol 50%) were studied. The final formulation was tested for purity, identity and stability in saline. Initial in vivo evaluation of [18F]AlF-DFH17 was performed in normal rats by PET/CT. RESULTS: The scaled-up production of [18F]AlF-DFH17 was performed in high radiochemical and chemical purities in an overall radiochemical yield of 22-38% (at end-of-synthesis) within 60 min. The final formulation was stable in saline at different radioactive concentrations for 8 h. PET evaluation in rats revealed high lung-to-background ratios and no defluorination in vivo up to 1 h post-injection. CONCLUSION: The novel radioconjugate [18F]AlF-DFH17 appears to be a promising PET ligand for pulmonary microcirculation imaging.

Positive and Negative Affect Is Related to Experiencing Chest Pain During Exercise-Induced Myocardial Ischemia.

OBJECTIVE: Silent myocardial ischemia is thought to be associated with worse cardiovascular outcomes due to a lack of perception of pain cues that initiate treatment seeking. Negative affect (NA) has been associated with increased pain reporting and positive affect (PA) with decreased pain reporting, but these psychological factors have not been examined within the context of myocardial ischemia. This study evaluated the associations between PA, NA, and chest pain reporting in patients with and without ischemia during exercise testing. METHODS: A total of 246 patients referred for myocardial perfusion single-photon emission computed tomography exercise stress testing completed the positive and negative affect schedule-expanded version, a measure of PA and NA. Presence of chest pain and myocardial ischemia were evaluated using standardized protocols. RESULTS: Logistic regression analyses revealed that for every 1-point increase in NA, there was a 13% higher chance for ischemic patients (odds ratio [OR] = 1.13; 95% confidence interval [CI] = 1.02 to 1.26) and an 11% higher chance in nonischemic patients (OR = 1.11; 95% CI = 1.03 to 1.19) to report chest pain. A significant interaction of PA and NA on chest pain reporting (ß = 0.02; 95% CI = 0.002 to 0.031) was also observed; nonischemic patients with high NA and PA reported more chest pain (57%) versus patients with low NA and low PA (13%), with high NA and low PA (17%), and with high PA and low NA (7%). CONCLUSIONS: Patients who experience higher NA are more likely to report experiencing chest pain. In patients without ischemia, high NA and PA was also associated with a higher likelihood of reporting chest pain. Results suggest that high levels of PA as well as NA may increase the experience and/or reporting of chest pain.

The impact of metabolic syndrome and endothelial dysfunction on exercise-induced cardiovascular changes.

OBJECTIVE: There is limited information regarding the synergistic or additive effects of metabolic syndrome (MS) and endothelial dysfunction (ED) on cardiovascular disease (CVD). Altered cardiovascular responses to exercise have been shown to predict future cardiovascular events as well as assess autonomic function. The present study evaluated the impact of MS and brachial artery reactivity (a proxy of ED) on peak exercise-induced cardiovascular changes. DESIGN AND METHODS: Individuals (n = 303) undergoing a standard nuclear medicine exercise stress test were assessed for MS. Participants underwent a Forearm Hyperaemic Reactivity test and were considered to have dysfunctional reactivity if their rate of uptake ratio (RUR) was <3.55. Resting and peak blood pressure (BP) and heart rate (HR) were measured. Reactivity was calculated as the difference between peak and resting measures. RESULTS: Analyses, adjusting for age, sex, resting HR, total metabolic equivalents (METs), and a history of major CVD, revealed a main effect of MS (F = 5.51, η(2) = 0.02, P = 0.02) and RUR (F = 6.69, η(2) = 0.02, P = 0.01) on HR reactivity, such that patients with MS and/or poor RUR had reduced HR reactivity. There were no interactive effects of RUR and MS. There were no effects of RUR or MS on systolic BP (SBP) or diastolic BP (DBP) reactivity or rate pressure product (RPP) reactivity. CONCLUSIONS: The presence of decreased HR reactivity among participants with MS or poor brachial artery reactivity, combined with the lack of difference in other exercise-induced cardiovascular changes, indicates that these patients may have some degree of parasympathetic dysregulation. Further longitudinal studies are needed to understand the long-term implications of MS and endothelial abnormalities in this context.

Differential short-term repeated forearm hyperaemic reactivity in coronary artery disease patients compared to healthy low risk participants.

The hyperaemic response of the forearm is a widely used technique to assess the vascular reactivity. Little is known about the short-term reproducibility and the possible exhaustion of this response in normal or diseased states. As such, the current study was conducted to assess this phenomenon using a unique nuclear medicine- (NM-) based technique. 19 patients with coronary artery disease (CAD) undergoing NM exercise stress tests and 15 low risk (LR) participants completed 2 reactive hyperaemia tests, using a SPECT-based technique, separated by 15 min. Analyses revealed that CAD patients had lower hyperaemic responses than LR participants (P < .001), and that there was a significant group × time interaction (P < .005), such that LR participants showed a larger decrease in the reactivity (5.2 ± 0.4 to 3.6 ± 0.4) than the CAD patients (2.9 ± 0.3 to 2.6 ± 0.3). These results suggest that there is a variability, due to disease states, in the reproducibility of the hypaeremic reactivity. This needs to be taken into account in short-term repeated measure studies.

The Relationship between Multiple Health Behaviours and Brachial Artery Reactivity.

Background. The effects of smoking, alcohol consumption, obesity, and a sedentary lifestyle on endothelial function (EF) have only been examined separately. The relative contributions of these behaviours on EF have therefore not been compared. Purpose. To compare the relative associations between these four risk factors and brachial artery reactivity in the same sample. Methods. 328 patients referred for single-photon emission computed tomography (SPECT) exercise stress tests completed a nuclear-medicine-based forearm hyperaemic reactivity test. Self-reported exercise behaviour, smoking habits, and alcohol consumption were collected and waist circumference was measured. Results. Adjusting for relevant covariates, logistic regression analyses revealed that waist circumference, abstinence from alcohol, and past smoking significantly predicted poor brachial artery reactivity while physical activity did not. Only waist circumference predicted continuous variations in EF. Conclusions. Central adiposity, alcohol consumption, and smoking habits but not physical activity are each independent predictors of poor brachial artery reactivity in patients with or at high risk for cardiovascular disease.

Tracer kinetics of forearm endothelial function: comparison of an empirical method and a quantitative modeling technique.

Forearm Endothelial Function (FEF) is a marker that has been shown to discriminate patients with cardiovascular disease (CVD). FEF has been assessed using several parameters: the Rate of Uptake Ratio (RUR), EWUR (Elbow-to-Wrist Uptake Ratio) and EWRUR (Elbow-to-Wrist Relative Uptake Ratio). However, the modeling functions of FEF require more robust models. The present study was designed to compare an empirical method with quantitative modeling techniques to better estimate the physiological parameters and understand the complex dynamic processes. The fitted time activity curves of the forearms, estimating blood and muscle components, were assessed using both an empirical method and a two-compartment model. Although correlational analyses suggested a good correlation between the methods for RUR (r=.90) and EWUR (r=.79), but not EWRUR (r=.34), Altman-Bland plots found poor agreement between the methods for all 3 parameters. These results indicate that there is a large discrepancy between the empirical and computational method for FEF. Further work is needed to establish the physiological and mathematical validity of the 2 modeling methods.

Quantitative hyperemic reactivity in opposed limbs during myocardial perfusion imaging: a new marker of coronary artery disease.

OBJECTIVES: We sought to evaluate the feasibility and validity of a new method to quantify the hyperemic response of the forearms that can be incorporated into a rest myocardial perfusion protocol. BACKGROUND: Evaluation of the hyperemic response could provide useful clinical information in the detection and risk stratification of atherosclerotic vascular disease. METHODS: Patients with proven coronary artery disease (CAD) (n = 46) were compared with low-risk subjects without such evidence (n = 47). A regular dose of Myoview was injected after 5 min of right arm ischemia. Three dimensionless parametric ratios (right/left) were derived from the analysis of activity-time curves of the hyperemic right forearm and that of the contralateral left forearm. RESULTS: The maximal ingress upslope ratio was 40% lower in the CAD group (3.0 +/- 0.2 vs. 4.2 +/- 0.3, p < 0.0005), and the integral to peak ratio was also lower (23 +/- 4 vs. 52 +/- 11, p < 0.01), whereas the peak activity ratio was nonsignificantly lower (3.0 +/- 0.3 vs. 3.8 +/- 0.3, p = 0.07). Using a value of 3.55 for the maximal upslope ratio, this approach could predict the presence of CAD with a sensitivity of 0.70 and a specificity of 0.60. CONCLUSIONS: This simple and noninvasive method is feasible and can discriminate between patients with known CAD and those at low risk of atherosclerosis. Refinements of this approach and its inclusion in larger clinical trials are needed to determine whether it could provide additional value to myocardial scintigraphic imaging.