18F-FDG PET in Myocardial Viability Assessment: A Practical and Time-Efficient Protocol.

We assessed image quality using a practical and time-efficient protocol for intravenous glucose loading and insulin injection before administration of 18F-FDG for PET myocardial viability evaluation in patients with ischemic cardiomyopathy (ICM), with and without type 2 diabetes mellitus. Methods: The metabolic preparation period (MPP) or optimal cardiac 18F-FDG uptake was determined from the time of intravenous infusion of 12.5 or 25 g of 50% dextrose to the time of 18F-FDG injection. Cardiac 18F-FDG image quality was evaluated according to a 5-point scoring system (from 5, excellent, to 1, nondiagnostic) by 2 independent observers. In cases of disagreement, consensus was achieved in a joint reading. Fifteen patients with ICM who underwent oral glucose loading and intravenous insulin administration served as a reference for MPP comparisons. Results: Fifty-nine consecutive patients (age, 63 ± 10 y; 48 men and 11 women) underwent rest 99mTc-tetrofosmin SPECT/CT and 18F-FDG PET/CT for the evaluation of myocardial viability. 18F-FDG image quality was scored as excellent in 42%, very good in 36%, good in 17%, fair in 3%, and nondiagnostic in 2%. When diabetic and nondiabetic patients were compared, the quality scores were excellent in 29% versus 76%, very good in 41% versus 18%, good in 24% versus 6%, fair in 4% versus 0%, and nondiagnostic in 2% versus 0%. The mean (±SD) quality score was 4.12 ± 0.95, and overall it was better in nondiabetic than in diabetic patients (4.71 ± 0.59 vs. 3.88 ± 0.96; P < 0.0001). Notably, the average MPP was significantly less with intravenous glucose loading than with oral glucose loading (51 ± 15 min vs. 132 ± 29 min; P < 0.0001), paralleled by higher insulin doses (6.3 ± 2.2 U vs. 2.0 ± 1.69 U; P < 0.001). Conclusion: Using a practical and time-efficient protocol for intravenous glucose loading and insulin administration before 18F-FDG injection reduces the MPP by 61% as compared with an oral glucose challenge and affords good-to-excellent image quality in 95% of ICM patients.

CCR2 Positron Emission Tomography for the Assessment of Abdominal Aortic Aneurysm Inflammation and Rupture Prediction.

BACKGROUND: The monocyte chemoattractant protein-1/CCR2 (chemokine receptor 2) axis plays an important role in abdominal aortic aneurysm (AAA) pathogenesis, with effects on disease progression and anatomic stability. We assessed the expression of CCR2 in a rodent model and human tissues, using a targeted positron emission tomography radiotracer (64Cu-DOTA-ECL1i). METHODS: AAAs were generated in Sprague-Dawley rats by exposing the infrarenal, intraluminal aorta to PPE (porcine pancreatic elastase) under pressure to induce aneurysmal degeneration. Heat-inactivated PPE was used to generate a sham operative control. Rat AAA rupture was stimulated by the administration of ß-aminopropionitrile, a lysyl oxidase inhibitor. Biodistribution was performed in wild-type rats at 1 hour post tail vein injection of 64Cu-DOTA-ECL1i. Dynamic positron emission tomography/computed tomography imaging was performed in rats to determine the in vivo distribution of radiotracer. RESULTS: Biodistribution showed fast renal clearance. The localization of radiotracer uptake in AAA was verified with high-resolution computed tomography. At day 7 post-AAA induction, the radiotracer uptake (standardized uptake value [SUV]=0.91±0.25) was approximately twice that of sham-controls (SUV=0.47±0.10; P<0.01). At 14 days post-AAA induction, radiotracer uptake by either group did not significantly change (AAA SUV=0.86±0.17 and sham-control SUV=0.46±0.10), independent of variations in aortic diameter. Competitive CCR2 receptor blocking significantly decreased AAA uptake (SUV=0.42±0.09). Tracer uptake in AAAs that subsequently ruptured (SUV=1.31±0.14; P<0.005) demonstrated uptake nearly twice that of nonruptured AAAs (SUV=0.73±0.11). Histopathologic characterization of rat and human AAA tissues obtained from surgery revealed increased expression of CCR2 that was co-localized with CD68+ macrophages. Ex vivo autoradiography demonstrated specific binding of 64Cu-DOTA-ECL1i to CCR2 in both rat and human aortic tissues. CONCLUSIONS: CCR2 positron emission tomography is a promising new biomarker for the noninvasive assessment of AAA inflammation that may aid in associated rupture prediction.

Assessment of Targeted Nanoparticle Assemblies for Atherosclerosis Imaging with Positron Emission Tomography and Potential for Clinical Translation.

Nanoparticles have been assessed in preclinical models of atherosclerosis for detection of plaque complexity and treatment. However, their successful clinical translation has been hampered by less than satisfactory plaque detection and lack of a general strategy for assessing the translational potential of nanoparticles. Herein, nanoparticles based on comb-co-polymer assemblies were synthesized through a modular construction approach with precise control over the conjugation of multiple functional building blocks for in vivo evaluation. This high level of design control also allows physicochemical properties to be varied in a controllable fashion. Through conjugation of c-atrial natriuretic factor (CANF) peptide and radiolabeling with 64Cu, the 64Cu-CANF-comb nanoparticle was assessed for plaque imaging by targeting natriuretic peptide clearance receptor (NPRC) in a double-injury atherosclerosis model in rabbits. The prolonged blood circulation and enhanced binding capacity of 64Cu-CANF-comb nanoparticles provided sensitive and specific imaging of NPRC overexpressed in atherosclerotic lesions by positron emission tomography at intervals during the progression of the disease. Ex vivo tissue validation using autoradiography and immunostaining on human carotid endarterectomy specimens demonstrated specific binding of 64Cu-CANF-comb to human NPRC receptors. Taken together, this study not only shows the potential of NPRC-targeted 64Cu-CANF-comb nanoparticles for increased sensitivity to an epitope that increases during atherosclerosis plaque development but also provides a useful strategy for the general design and assessment of the translational potential of nanoparticles in cardiovascular imaging.

Reproducibility of creatine kinase reaction kinetics in human heart: a (31) P time-dependent saturation transfer spectroscopy study.

Creatine kinase (CK) is essential for the buffering and rapid regeneration of adenosine triphosphate (ATP) in heart tissue. Herein, we demonstrate a (31) P MRS protocol to quantify CK reaction kinetics in human myocardium at 3 T. Furthermore, we sought to quantify the test-retest reliability of the measured metabolic parameters. The method localizes the (31) P signal from the heart using modified one-dimensional image-selected in vivo spectroscopy (ISIS), and a time-dependent saturation transfer (TDST) approach was used to measure CK reaction parameters. Fifteen healthy volunteers (22 measurements in total) were tested. The CK reaction rate constant (kf ) was 0.32 ± 0.05 s(-1) and the coefficient of variation (CV) was 15.62%. The intrinsic T1 for phosphocreatine (PCr) was 7.36 ± 1.79 s with CV = 24.32%. These values are consistent with those reported previously. The PCr/ATP ratio was equal to 1.94 ± 0.15 with CV = 7.73%, which is within the range of healthy subjects. The reproducibility of the technique was tested in seven subjects and inferred parameters, such as kf and T1 , exhibited good reliability [intraclass correlation coefficient (ICC) of 0.90 and 0.79 for kf and T1 , respectively). The reproducibility data provided in this study will enable the calculation of the power and sample sizes required for clinical and research studies. The technique will allow for the examination of cardiac energy metabolism in clinical and research studies, providing insight into the relationship between energy deficit and functional deficiency in the heart.

Impact of sex on the heart's metabolic and functional responses to diabetic therapies.

Increased myocardial lipid delivery is a determinant of myocardial substrate metabolism and function in animal models of type 2 diabetes (T2DM). Sex also has major effects on myocardial metabolism in the human heart. Our aims were to determine whether 1) sex affects the myocardial metabolic response to lipid lowering in T2DM, 2) altering lipid [fatty acid (FA) or triglyceride] delivery to the heart would lower the elevated myocardial lipid metabolism associated with T2DM, and 3) decreasing lipid delivery improves diastolic dysfunction in T2DM. To this end, we studied 78 T2DM patients (43 women) with positron emission tomography, echocardiography, and whole body tracer studies before and 3 mo after randomization to metformin (MET), metformin + rosiglitazone (ROSI), or metformin + Lovaza (LOV). No treatment main effects were found for myocardial substrate metabolism, partly because men and women often had different responses to a given treatment. In men, MET decreased FA clearance, which was linked to increased plasma FA levels, myocardial FA utilization and oxidation, and lower myocardial glucose utilization. In women, ROSI increased FA clearance, thereby decreasing plasma FA levels and myocardial FA utilization. Although LOV did not change triglyceride levels, it improved diastolic function, particularly in men. Group and sex also interacted in determining myocardial glucose uptake. Thus, in T2DM, different therapeutic regimens impact myocardial metabolism and diastolic function in a sex-specific manner. This suggests that sex should be taken into account when designing a patient's diabetes treatment.

Anatomic versus physiologic assessment of coronary artery disease. Role of coronary flow reserve, fractional flow reserve, and positron emission tomography imaging in revascularization decision-making.

Angiographic severity of coronary artery stenosis has historically been the primary guide to revascularization or medical management of coronary artery disease. However, physiologic severity defined by coronary pressure and/or flow has resurged into clinical prominence as a potential, fundamental change from anatomically to physiologically guided management. This review addresses clinical coronary physiology-pressure and flow-as clinical tools for treating patients. We clarify the basic concepts that hold true for whatever technology measures coronary physiology directly and reliably, here focusing on positron emission tomography and its interplay with intracoronary measurements.

Assessment of myocardial triglyceride oxidation with PET and 11C-palmitate.

BACKGROUND: The goal of this study was to test whether myocardial triglyceride (TG) turnover including oxidation of TG-derived fatty acids (FA) could be assessed with PET and (11)C-palmitate. METHODS AND RESULTS: A total of 26 dogs were studied fasted (FAST), during Intralipid infusion (IL), during a hyperinsulinemic-euglycemic clamp without (HIEG), or with Intralipid infusion (HIEG + IL). (11)C-palmitate was injected, and 45 minutes were allowed for labeling of myocardial TG pool. 3D PET data were then acquired for 60 minutes, with first 15 minutes at baseline followed by 45 minutes during cardiac work stimulated with constant infusion of either phenylephrine (FAST, n = 6; IL, n = 6; HIEG + IL, n = 6) or dobutamine (FAST, n = 4; HIEG, n = 4). Myocardial (11)C washout during adrenergic stimulation (AS) was fitted to a mono-exponential function (Km(PET)). To determine the source of this (11)C clearance, Km(PET) was compared to direct coronary sinus-arterial measurements of total (11)C activity, (11)C-palmitate, and (11)CO(2). Before AS, PET curves in all groups were flat indicating absence of net clearance of (11)C activity from heart. In both FAST groups, AS resulted in negligible net (11)C activity and (11)CO(2) production higher than net (11)C-palmitate uptake. AS with phenylephrine resulted in net myocardial uptake of total (11)C activity and (11)C-palmitate in IL and HIEG + IL, and (11)CO(2) production lower than (11)C-palmitate uptake. In contrast, AS with dobutamine in HIEG resulted in net clearance of all (11)C metabolites (total (11)C activity, (11)C-palmitate and (11)CO(2)) with (11)CO(2) contributing 66% to endogenous FA oxidation. The AS resulted in significant Km(PET) in all the groups, except HIEG + IL. However, positive correlation between Km(PET) and (11)CO(2) was observed only in HIEG (R (2) = 0.83, P = .09). CONCLUSIONS: This is the first study to demonstrate that using PET and pre-labeling of intracardiac TG pool with (11)C-palmitate, noninvasive assessment of myocardial TG use is feasible under metabolic conditions that favor endogenous TG use such as increased metabolic demand (beta-adrenergic stimulation of cardiac work) with limited availability of exogenous substrate (HIEG).

Assessment of myocardial oxygen extraction fraction and perfusion reserve with BOLD imaging in a canine model with coronary artery stenosis.

PURPOSE: To determine the feasibility of T2-weighted BOLD imaging for estimating regional myocardial oxygen extraction fraction (OEF) and approximating perfusion reserve (MPR) simultaneously in a canine model with moderate coronary artery stenosis. MATERIALS AND METHODS: Eight mongrel dogs with moderate coronary artery stenosis underwent BOLD imaging at rest and during dipyridamole-induced hyperemia, using a turbo spin echo (TSE) sequence. Based on a two-compartment model, myocardial OEF(hyperemia) was calculated with the corresponding T2. MPR could be approximated based on Fick's law. RESULTS: During responsive hyperemia, a regional hypointensity was observed in the abnormally perfused myocardium, reflecting a relatively smaller myocardial T2 increase (3.06% +/- 2.74%, in contrast to 10.19% +/- 4.12% in the normal region). The average OEFs in the normally and abnormally perfused myocardial territories were 0.21 +/- 0.11 and 0.43 +/- 0.12, respectively. For the MPR approximated from the BOLD imaging, a strong correlation (R = 0.9) in the normal myocardium and a good correlation (R = 0.6) distal to the stenosis were obtained compared to microsphere results. CONCLUSION: In a canine model with moderate coronary artery stenosis, TSE-based BOLD imaging can quantitatively estimate the regional OEF(hyperemia) and approximate the MPR, and can distinguish segments perfused by defected coronary artery.

Assessment of myocardial metabolism in diabetic rats using small-animal PET: a feasibility study.

UNLABELLED: This feasibility study was undertaken to determine whether kinetic modeling in conjunction with small-animal PET could noninvasively quantify alterations in myocardial perfusion and substrate metabolism in rats. METHODS: All small-animal PET was performed on either of 2 tomographs. Myocardial blood flow and substrate metabolism were measured in 10 male Zucker diabetic fatty rats (ZDF, fa/fa) and 10 lean littermates (Lean, Fa/+) using (15)O-water, 1-(11)C-glucose, 1-(11)C-acetate, and 1-(11)C-palmitate. Animals were 12.0 +/- 1.4-wk old. RESULTS: Consistent with a type 2 diabetic phenotype, the ZDF animals showed higher plasma hemoglobin A(1c), insulin, glucose, and free fatty acid (FFA) levels than their lean controls. Myocardial glucose uptake (mL/g/min) was not significantly different between the 2 groups. However, higher glucose plasma levels in the ZDF rats resulted in higher myocardial glucose utilization (nmol/g/min) (Lean, 629 +/- 785, vs. ZDF, 1,737 +/- 1,406; P = 0.06). Similarly, myocardial FFA uptake (mL/g/min) was not significantly different between the 2 groups, (Lean, 0.51 +/- 28, vs. ZDF, 0.72 +/- 0.19; P = not significant) However, due to higher FFA plasma levels, utilization and oxidation (nmol/g/min) were significantly higher in the ZDF group (Lean, 519 +/- 462, vs. ZDF, 1,623 +/- 712, P < .001; and Lean, 453 +/- 478, vs. ZDF, 1,636 +/- 730, P < .01). CONCLUSION: Noninvasive measurements of myocardial substrate metabolism in ZDF rats using small-animal PET are consistent with the expected early metabolic abnormalities that occur in this well-characterized model of type 2 diabetes mellitus. Thus, small-animal PET demonstrates significant promise in providing a means to link the myocardial metabolic abnormalities that occur in rat of disease with the human condition.

Assessment of myocardial blood flow using 15O-water and 1-11C-acetate in rats with small-animal PET.

UNLABELLED: This feasibility study was undertaken to determine whether myocardial blood flow (MBF, mL/g/min) could be quantified noninvasively in small rodents using microPET and 15O-water or 1-11C-acetate. METHODS: MBF was measured in 18 healthy rats using PET and 15O-water (MBF-W) under different interventions and compared with direct measurements obtained with microspheres (MBF-M). Subsequently, MBF was estimated in 24 rats at rest using 1-11C-acetate (MBF-Ace) and compared with measurements obtained with 15O-water. Using factor analysis, images were processed to obtain 1 blood and 1 myocardial time-activity curve per tracer per study. MBF-W was calculated using a well-validated 1-compartment kinetic model. MBF-Ace was estimated using a simple 1-compartment model to estimate net tracer uptake, K1 (K1 (mL/g/min) = MBF.E; E = first-pass myocardial extraction of 1-11C-acetate) and washout (k2 (min(-1))) along with F(BM) (spillover correction) after fixing F(MM) (partial-volume correction) to values obtained from 15O-water modeling. K1 values were converted to MBF values using a first-pass myocardial extraction/flow relationship measured in rats (E = 1.0-0.74.exp(-1.13/MBF)). RESULTS: In the first study, MBF-W correlated well with MBF-M (y = 0.74x + 0.96; n = 18, r = 0.91, P < 0.0001). However, the slope was different than unity, P < 0.05). Refitting of the data after forcing the intercept to be zero resulted in a nonbias correlation between MBF-W and MBF-M (y = 0.95x + 0.0; n = 18, r = 0.86, P < 0.0001) demonstrating that the underestimation of the slope could be attributed to the overestimation of MBF-W for 2 MBF-M values lower than 1.50 mL/g/min. In the second study, MBF-Ace values correlated well with MBF-W with no underestimation of MBF (y = 0.91x + 0.35; n = 24, r = 0.87, P < 0.0001). CONCLUSION: MBF can be quantified by PET using (15)O-water or 1-11C-acetate in healthy rats. Future studies are needed to determine the accuracy of the methods in low-flow states and to develop an approach for a partial-volume correction when 1-11C-acetate is used.

Alterations in left ventricular structure and function in young healthy obese women: assessment by echocardiography and tissue Doppler imaging.

OBJECTIVES: This study was designed to determine the effects of obesity on left ventricular (LV) structure and function in young obese women. BACKGROUND: Severe prolonged obesity in older adults results in increased plasma volume, eccentric LV hypertrophy, and systolic and diastolic dysfunction. Obese women are at increased risk for the development of heart failure. However, the effects of the obesity on cardiac structure and function in young, otherwise-healthy women are controversial. METHODS: Fifty-one women were evaluated: 20 were obese (body mass index [BMI] > or =30 kg/m(2)) and 31 were non-obese (BMI <30 kg/m(2)). Left ventricular structure and systolic and diastolic function were assessed by two-dimensional echocardiography and tissue Doppler imaging, including the load-independent systolic myocardial velocity (Sm global) and early diastolic myocardial velocity (Em global), respectively. The effects of BMI on LV structure and function were assessed using multivariate regression analyses. RESULTS: Obese women had higher end-diastolic septal and posterior wall thickness, LV mass, and relative wall thickness than non-obese women; BMI values showed significant correlations with these variables (r = 0.58, p < 0.0001; r = 0.50, p < 0.0002; r = 0.52, p < 0.0001, and r = 0.40, p < 0.005, respectively). The Sm global and Em global were lower in obese women, suggesting systolic and diastolic function are decreased; both were negatively correlated with BMI (r = -0.43, p <. 002 and r = -0.61, p < 0.0001, respectively). Multivariate analysis showed BMI was the only independent predictor of relative wall thickness, Sm global, and Em global. CONCLUSIONS: Obesity in young otherwise-healthy women is associated with concentric LV remodeling and decreased systolic and diastolic function. These early abnormalities in LV structure and function may have important implications for explaining the myocardial dysfunction that is associated with increased cardiovascular morbidity and mortality caused by obesity.

Noninvasive, quantitative assessment of left ventricular function in ischemic cardiomyopathy.

BACKGROUND: Coronary artery disease characteristically impacts left ventricular (LV) function on a regional basis, although ultimately global function may be affected as well. Echocardiography is commonly clinically used for the assessment of regional function; however, it is only semiquantitative and in its current iteration is only two-dimensional in nature. Magnetic resonance imaging (MRI) with tissue tagging offers the possibility for noninvasive, three-dimensional (3D) assessment of transmural and segmental left ventricular strain and, thereby, function. Accordingly, we have explored methodologies to accurately and quantitatively characterize regional systolic function in three dimensions in patients with ischemic heart disease using MRI. MATERIALS AND METHODS: MRI radiofrequency tissue tagging was performed at rest and during dobutamine administration (10 mg/kg/min) on 10 normal volunteers (age: 26 +/- 6) and 8 patients with severe ischemic cardiomyopathy (age: 60 +/- 5, EF 26 +/- 11%). Three-dimensional global and regional systolic strain calculations were made based on 3D myocardial point displacements and compared with conventional measures. RESULTS: Global left ventricular strains were significantly decreased in ischemic patients at rest (0.14 +/- 0.04 versus 0.25 +/- 0.02, P < 0.001) and with dobutamine (0.14 +/- 0.03 versus 0.29 +/- 0.03, P < 0.001). In the regional analysis (216 LV wall segments) this methodology accurately differentiated normal from abnormally contracting regions. CONCLUSIONS: Noninvasive dobutamine MRI tissue tagging with calculation of 3D regional strains has significant promise as a clinical tool which is capable of the identification, quantification, and display of regionally varying ventricular function.