CAV results in diffuse concentric intimal thickening of the epicardial vessels affecting both the proximal and distal vessels as well as the microcirculation.3 This progressive luminal narrowing and loss of vasodilatory capacity culminates in myocardial ischemia and contractile dysfunction. Immunemediated injury plays a significant role in the development of epicardial vessel stenosis in addition to traditional risk factors. 4 Clinical symptoms such as angina are typically absent in cases of CAV because of allograft denervation, and therefore annual screening is used in most centers.Recent guidelines recommend periodic invasive coronary angiography for at least the first 3 to 5 years after transplantation. 5 However, this is inconvenient and adds risk. Hence, many centers have elected to monitor patients with noninvasive testing, but this strategy may be suboptimal because of the lower sensitivity for the detection of early CAV. 6,7 Rubidium-82 (Rb-82) positron emission tomography (PET) myocardial perfusion imaging is a noninvasive imaging modality that has the ability to quantify myocardial blood flow (MBF) 8 and has been shown to have prognostic value in patients being assessed for ischemia.9-11 This technique may facilitate earlier detection of CAV and thus may have prognostic value in HT patients. The objective of this study was to evaluate the prognostic value of Rb-82 PET in patients with a history of HT.Background-Cardiac allograft vasculopathy is a key prognostic determinant after heart transplant. Detection and risk stratification of patients with cardiac allograft vasculopathy are problematic. Positron emission tomography using rubidium-82 allows quantification of absolute myocardial blood flow and may have utility for risk stratification in this population. Methods and Results-Patients with a history of heart transplant undergoing dipyridamole rubidium-82 positron emission tomography were prospectively enrolled. Myocardial perfusion and left ventricular ejection fraction were recorded. Absolute flow quantification at rest and after dipyridamole stress as well as the ratio of mean global flow at stress and at rest, termed myocardial flow reserve, were calculated. Patients were followed for all-cause death, acute coronary syndrome, and heart failure hospitalization. A total of 140 patients (81% men; median age, 62 years; median follow-up, 18.2 months) were included. There were 14 events during follow-up (9 deaths, 1 acute coronary syndrome, and 4 heart failure admissions). In addition to baseline clinical variables (estimated glomerular filtration rate, previously documented cardiac allograft vasculopathy), relative perfusion defects, mean myocardial flow reserve, and mean stress myocardial blood flow were significant predictors of adverse outcome. Conclusions-Abnormalities on rubidium-82 positron emission tomography were predictors of adverse events in heart transplant patients. Larger prospective studies are required to confirm these findings. (Circ Cardiovasc Imaging. 2014;7:930-937.)

Respiratory motion can induce artifacts in cardiac PET/CT because of the misregistration of the CT attenuation map and emission data. Some solutions to the respiratory motion problem use 4-dimensional CT, but this increases patient radiation exposure. Realignment of 3-dimensional CT and PET images can remove apparent uptake defects caused by mispositioning of the PET emission data into the lung regions on the CT scan. This realignment is typically done as part of regular clinical quality assurance. We evaluated a method to improve on this standard approach, without increasing the radiation exposure to the patient, by acquiring a respiration-gated PET scan and separately aligning the 3-dimensional CT scan to each phase of the PET study. Methods: Three hundred ten clinical PET perfusion scans ( 82 Rb [n 5 187] and 13 N-ammonia [n 5 123]) were retrospectively assessed. Studies were respiration-gated, and motion was measured between inspiration and expiration phases. Those studies with motion $ 8 mm were evaluated for significant differences between inspiration and expiration. Studies with significant differences were reprocessed with the phase-alignment approach. The observed motion with 82 Rb and 13 N-ammonia for rest and stress imaging was also compared. Results: Twentythree scans (7.41%) had motion $ 8 mm, and 9 of these had significant differences between inspiration and expiration, suggesting the presence of respiratory artifacts. Phase-aligned respiratory motion compensation reduced this difference in 8 of 9 cases (89%). No significant differences were observed between 82 Rb and 13 N-ammonia, and motion during stress imaging was correlated with motion at rest (r 5 0.61, P , 0.001). Conclusion: Phase-aligned correction improves the consistency of PET/CT perfusion images by reducing discrepancies caused by respiratory motion. This new approach to CT-based attenuation correction has no additional patient radiation exposure and may improve the specificity of PET perfusion imaging. Accurat e attenuation correction (AC) is a major clinical advantage of PET, compared with SPECT, and has been well accepted when the attenuation map is formed using data from radioactive transmission sources. However, respiratory motion can induce artifacts in cardiac PET/CT because of misregistration of the CT attenuation map and emission data. Misregistration has been shown to occur in up to 40% of clinical cardiac PET/CT studies (1). The most common artifact is an apparent decrease in uptake in the anterior or lateral wall due to a mispositioning of the activity from the heart into the low-attenuating tissues of the lungs. Many studies have examined the effect of this misalignment and found that motion of 6-8 mm produces mild to moderate errors, and motion .8 mm leads to severe errors that may affect clinical interpretation (1,2). Several approaches have been suggested to reduce the impact of this problem including simple realignment of the CT scan and the PET data (2,3), slow CT scans (4), and methods that estimate the motion from r...

UCP3 (uncoupling protein-3) mitigates mitochondrial ROS (reactive oxygen species) production, but the mechanisms are poorly understood. Previous studies have also examined UCP3 effects, including decreased ROS production, during metabolic states when fatty acid oxidation is high (e.g. a fasting state). However, the role of UCP3 when carbohydrate oxidation is high (e.g. fed state) has remained largely unexplored. In the present study, we show that mitochondrial-bound HK (hexokinase) II curtails oxidative stress and enhances aerobic metabolism of glucose in the fed state in a UCP3-dependent manner. Genetic knockout or inhibition of UCP3 significantly decreased mitochondrial-bound HKII. Furthermore, UCP3 was required for the HKII-mediated decrease in mitochondrial ROS emission. Intriguingly, the UCP3-mediated modulation of mitochondria-associated HKII was only observed in cells cultured under high-glucose conditions. UCP3 was required to maintain high rates of aerobic metabolism in high-glucose-treated cells and in muscle of fed mice. Deficiency in UCP3 resulted in a metabolic shift that favoured anaerobic glycolytic metabolism, increased glucose uptake and increased sensitivity to oxidative challenge. PET (positron emission tomography) of [18F]fluoro-deoxyglucose uptake confirmed these findings in UCP3-knockout and wild-type mice. Collectively, our findings link the anti-oxidative and metabolic functions of UCP3 through a surprising molecular connection with mitochondrial-bound HKII.

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Cyclic adenosine monophosphate (cAMP) is the common second messenger in signal-transduction cascades originating at a number of monoamine receptors involved in neurotransmission, cardiac function and smooth muscle contraction. Altered regulation of cAMP synthesis (at receptors, G-protein subunits or adenylyl cyclase) and breakdown by phosphodiesterase (PDE) enzymes have been implicated in a number of pathologies. The PDE4 inhibitor (R)-rolipram, and the less active (S)- enantiomer, have been labeled with carbon-11 and characterized by in vivo and in vitro experiments for use in the evaluation of altered PDE4 levels in the brain and cardiac tissues. (R)-[11C]Rolipram has been shown to bind selectively to PDE4 over other PDE isozymes, with specific binding reflecting approximately 80 and 40% of the total detected radioactivity in the rat brain and the heart, respectively. Tracer retention in PDE4-rich tissues is increased by cAMP-elevating treatments, as detected by in vivo PET studies and ex vivo biodistribution experiments. In vivo PET imaging studies display strong region-specific signal in the brain and heart, as evaluated in rats, pigs, monkeys and humans. Impaired cAMP-mediated signaling was observed in animal models of aging, obesity, anthracycline-induced cardiotoxicity and myocardial infarction using (R)-[11C]rolipram. Given the critical role of cAMP in multiple hormonal pathways, the good safety profile and well-characterized pharmacokinetics, (R)-[11C]rolipram PET imaging provides a novel tool for serial monitoring of cAMP-mediated signaling at the PDE4 level, yielding insight into pathological progression with potential for directing therapy.

ACE inhibitors are considered first line of treatment in patients with many forms of chronic kidney disease (CKD). Other antihypertensives such as calcium channel blockers achieve similar therapeutic effectiveness in attenuating hypertension-related renal damage progression. Our objective was to explore the value of positron emission tomography (PET) imaging of renal AT1 receptor (AT1R) to guide therapy in the 5/6 subtotal-nephrectomy (Nx) rat model of CKD. Ten weeks after Nx, Sprague-Dawley rats were administered 10mg/kg/d enalapril (NxE), 30mg/kg/d diltiazem (NxD) or left untreated (Nx) for an additional 8–10 weeks. Kidney AT1R expression was assessed using in vivo [18F]fluoropyridine-losartan PET and in vitro autoradiography. Compared to shams, Nx rats exhibited higher systolic blood pressure that was reduced by both enalapril and diltiazem. At 18–20 weeks, plasma creatinine and albuminuria were significantly increased in Nx, reduced to sham levels in NxE, but enhanced in NxD rats. Enalapril treatment decreased kidney angiotensin II whereas diltiazem induced significant elevations in plasma and kidney levels. Reduced PET renal AT1R levels in Nx were normalized by enalapril but not diltiazem, and results were supported by autoradiography. Reduction of renal blood flow in Nx was restored by enalapril, while no difference was observed in myocardial blood flow amongst groups. Enhanced left ventricle mass in Nx was not reversed by enalapril but was augmented with diltiazem. Stroke volume was diminished in untreated Nx compared to shams and restored with both therapies. [18F]Fluoropyridine-Losartan PET allowed in vivo quantification of kidney AT1R changes associated with progression of CKD and with various pharmacotherapies.

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