Human brown adipose tissue [(15)O]O2 PET imaging in the presence and absence of cold stimulus.

PURPOSE: Brown adipose tissue (BAT) is considered a potential target for combatting obesity, as it produces heat instead of ATP in cellular respiration due to uncoupling protein-1 (UCP-1) in mitochondria. However, BAT-specific thermogenic capacity, in comparison to whole-body thermogenesis during cold stimulus, is still controversial. In our present study, we aimed to determine human BAT oxygen consumption with [(15)O]O2 positron emission tomography (PET) imaging. Further, we explored whether BAT-specific energy expenditure (EE) is associated with BAT blood flow, non-esterified fatty acid (NEFA) uptake, and whole-body EE. METHODS: Seven healthy study subjects were studied at two different scanning sessions, 1) at room temperature (RT) and 2) with acute cold exposure. Radiotracers [(15)O]O2, [(15)O]H2O, and [(18)F]FTHA were given for the measurements of BAT oxygen consumption, blood flow, and NEFA uptake, respectively, with PET-CT. Indirect calorimetry was performed to assess differences in whole-body EE between RT and cold. RESULTS: BAT-specific EE and oxygen consumption was higher during cold stimulus (approx. 50 %); similarly, whole-body EE was higher during cold stimulus (range 2-47 %). However, there was no association in BAT-specific EE and whole-body EE. BAT-specific EE was found to be a minor contributor in cold induced whole-body thermogenesis (almost 1 % of total whole-body elevation in EE). Certain deep muscles in the cervico-thoracic region made a major contribution to this cold-induced thermogenesis (CIT) without any visual signs or individual perception of shivering. Moreover, BAT-specific EE associated with BAT blood flow and NEFA uptake both at RT and during cold stimulus. CONCLUSION: Our study suggests that BAT is a minor and deep muscles are a major contributor to CIT. In BAT, both in RT and during cold, cellular respiration is linked with circulatory NEFA uptake.

Myocardial blood flow and its transit time, oxygen utilization, and efficiency of highly endurance-trained human heart.

Highly endurance-trained athlete's heart represents the most extreme form of cardiac adaptation to physical stress, but its circulatory alterations remain obscure. In the present study, myocardial blood flow (MBF), blood mean transit time (MTT), oxygen extraction fraction (OEF) and consumption (MVO2), and efficiency of cardiac work were quantified in highly trained male endurance athletes and control subjects at rest and during supine cycling exercise using [(15)O]-labeled radiotracers and positron emission tomography. Heart rate and MBF were lower in athletes both at rest and during exercise. OEF increased in response to exercise in both groups, but was higher in athletes (70 ± 21 vs. 63 ± 11 % at rest and 86 ± 13 vs. 73 ± 10 % during exercise). MTT was longer and vascular resistance higher in athletes both at rest and during exercise, but arterial content of 2,3-diphosphoglycerate (oxygen affinity) was unchanged. MVO2 per gram of myocardium trended (p = 0.08) lower in athletes both at rest and during exercise, while myocardial efficiency of work and MVO2 per beat were not different between groups. Arterial levels of free fatty acids were ~twofold higher in athletes likely leading to higher myocardial fatty acid oxidation and hence oxygen cost, which may have blunted the bradycardia-induced decrease in MVO2. Finally, the observed group differences in MBF, OEF, MTT and vascular resistance remained significant also after they were controlled for differences in MVO2. In conclusion, in highly endurance-trained human heart, increased myocardial blood transition time enables higher oxygen extraction levels with a lower myocardial blood flow and higher vascular resistance. These physiological adaptations to exercise training occur independently of the level of oxygen consumption and together with training-induced bradycardia may serve as mechanisms to increase functional reserve of the human heart.

Effects of adenosine, exercise, and moderate acute hypoxia on energy substrate utilization of human skeletal muscle.

Glucose metabolism increases in hypoxia and can be influenced by endogenous adenosine, but the role of adenosine for regulating glucose metabolism at rest or during exercise in hypoxia has not been elucidated in humans. We studied the effects of exogenous adenosine on human skeletal muscle glucose uptake and other blood energy substrates [free fatty acid (FFA) and lactate] by infusing adenosine into the femoral artery in nine healthy young men. The role of endogenous adenosine was studied by intra-arterial adenosine receptor inhibition (aminophylline) during dynamic one-leg knee extension exercise in normoxia and acute hypoxia corresponding to ∼3,400 m of altitude. Extraction and release of energy substrates were studied by arterial-to-venous (A-V) blood samples, and total uptake or release was determined by the product of A-V differences and muscle nutritive perfusion measured by positron emission tomography. The results showed that glucose uptake increased from a baseline value of 0.2 ± 0.2 to 2.0 ± 2.2 µmol·100 g(-1)·min(-1) during adenosine infusion (P < 0.05) at rest. Although acute hypoxia enhanced arterial FFA levels, it did not affect muscle substrate utilization at rest. During exercise, glucose uptake was higher (195%) during acute hypoxia compared with normoxia (P = 0.058), and aminophylline had no effect on energy substrate utilization during exercise, despite that arterial FFA levels were increased. In conclusion, exogenous adenosine at rest and acute moderate hypoxia during low-intensity knee-extension exercise increases skeletal muscle glucose uptake, but the increase in hypoxia appears not to be mediated by adenosine.

Intrapericardial, but not extrapericardial, fat is an independent predictor of impaired hyperemic coronary perfusion in coronary artery disease.

OBJECTIVE: To measure intrapericardial fat (IPF), extrapericardial fat (EPF), and myocardial perfusion (MBF) in patients with and without coronary artery disease (CAD), hypothesizing that perfusion is more strongly associated with IPF because it is in direct anatomic contiguity with the myocardium or coronary arteries. METHODS AND RESULTS: Fat surrounding the heart may increase the risk of CAD and calcification, but little is known about the role of MBF in this relationship. The study included 107 patients with an intermediate likelihood of CAD. Positron emission tomography/computed tomography was used to measure IPF and EPF volumes and coronary artery calcium level, together with MBF at rest and during adenosine-induced hyperemia. Subsequently, all subjects underwent coronary angiography and were grouped for presence/absence of CAD and severity of myocardial hypoperfusion. IPF and EPF levels were higher in men and in patients with CAD (n=85) than in those without CAD (n=22) (P<0.001). EPF was increased regardless of the degree of stenoses (n=45), whereas IPF was selectively increased in subjects with obstructive stenoses (n=40). IPF and EPF levels were both associated with coronary artery calcium scores (R=0.25 and R=0.26, respectively; P<0.02), coronary flow reserve (R=-0.37 and R=-0.38, respectively; P<0.001), and hyperemic MBF (R=-0.36 and R=-0.44, respectively; P<0.0005). Male sex was a strong negative predictor of MBF. After discounting for confounders, myocardial hyperemic perfusion was predicted independently by sex, coronary artery calcium score, and IPF, but not EPF. CONCLUSIONS: CAD is accompanied by augmented fat depots surrounding the heart, which are negatively related to coronary flow hyperemia. Among fat depots, IPF was the only independent predictor of hyperemic MBF, supporting the hypothesis of a direct paracrine/vasocrine effect.

Skeletal muscle blood flow and oxygen uptake at rest and during exercise in humans: a pet study with nitric oxide and cyclooxygenase inhibition.

The aim of the present study was to determine the effect of nitric oxide and prostanoids on microcirculation and oxygen uptake, specifically in the active skeletal muscle by use of positron emission tomography (PET). Healthy males performed three 5-min bouts of light knee-extensor exercise. Skeletal muscle blood flow and oxygen uptake were measured at rest and during the exercise using PET with H(2)O(15) and (15)O(2) during: 1) control conditions; 2) nitric oxide synthase (NOS) inhibition by arterial infusion of N(G)-monomethyl-L-arginine (L-NMMA), and 3) combined NOS and cyclooxygenase (COX) inhibition by arterial infusion of L-NMMA and indomethacin. At rest, inhibition of NOS alone and in combination with indomethacin reduced (P < 0.05) muscle blood flow. NOS inhibition increased (P < 0.05) limb oxygen extraction fraction (OEF) more than the reduction in muscle blood flow, resulting in an ∼20% increase (P < 0.05) in resting muscle oxygen consumption. During exercise, muscle blood flow and oxygen uptake were not altered with NOS inhibition, whereas muscle OEF was increased (P < 0.05). NOS and COX inhibition reduced (P < 0.05) blood flow in working quadriceps femoris muscle by 13%, whereas muscle OEF and oxygen uptake were enhanced by 51 and 30%, respectively. In conclusion, by specifically measuring blood flow and oxygen uptake by the use of PET instead of whole limb measurements, the present study shows for the first time in humans that inhibition of NO formation enhances resting muscle oxygen uptake and that combined inhibition of NOS and COX during exercise increases muscle oxygen uptake.

Dual-gated cardiac PET-clinical feasibility study.

PURPOSE: Both respiratory and cardiac motions reduce image quality in myocardial imaging. For accurate imaging of small structures such as vulnerable coronary plaques, simultaneous cardiac and respiratory gating is warranted. This study tests the feasibility of a recently developed robust method for cardiac-respiratory gating. List-mode data with triggers from respiratory and cardiac cycles are rearranged into dual-gated segments and reconstructed with standard algorithms of a commercial PET/CT scanner. Cardiac gates were defined as three fixed phases and one variable diastolic phase. Chest motion was measured with a respiratory gating device and post-processed to determine gates. Preservation of quantification in dual-gated images was tested with an IEC whole-body phantom. METHODS: Minipig and human studies were performed to evaluate the feasibility of the method. In minipig studies, a coronary catheter with radioactive tip was guided in coronary artery for in vivo and ex vivo acquisitions. Dual gating in humans with suspected cardiac disorders was performed using 18-F-FDG as a tracer. RESULTS: The method was found feasible for in vivo imaging and the radioactive catheter tip was better resolved in gated images. In human studies, the dual gating was found feasible and easy for clinical routine. Maximal movement of myocardial surface in cranio-caudal direction was over 20 mm. The shape of myocardium was clearly different between the gates and papillary muscles become more visible in diastolic images. CONCLUSION: The first clinical experiences using robust cardiac-respiratory dual gating are encouraging. Further testing in larger clinical populations using tracers designed especially for plaque imaging is warranted.

Dual gated PET/CT imaging of small targets of the heart: method description and testing with a dynamic heart phantom.

BACKGROUND: In PET imaging respiratory and cardiac contraction motions interfere the imaging of heart. The aim was to develop and evaluate dual gating method for improving the detection of small targets of the heart. METHODS: The method utilizes two independent triggers which are sent periodically into list mode data based on respiratory and ECG cycles. An algorithm for generating dual gated segments from list mode data was developed. RESULTS: The test measurements showed that rotational and axial movements of point source can be separated spatially to different segments with well-defined borders. The effect of dual gating on detection of small moving targets was tested with a moving heart phantom. Dual gated images showed 51% elimination (3.6 mm out of 7.0 mm) of contraction motion of hot spot (diameter 3 mm) and 70% elimination (14 mm out of 20 mm) of respiratory motion. Averaged activity value of hot spot increases by 89% when comparing to non-gated images. Patient study of suspected cardiac sarcoidosis shows sharper spatial myocardial uptake profile and improved detection of small myocardial structures such as papillary muscles. CONCLUSIONS: The dual gating method improves detection of small moving targets in a phantom and it is feasible in clinical situations.

Myocardial Blood Flow and Metabolic Rate of Oxygen Measurement in the Right and Left Ventricles at Rest and During Exercise Using 15O-Labeled Compounds and PET.

Aims: Simultaneous measurement of right (RV) and left ventricle (LV) myocardial blood flow (MBF), oxygen extraction fraction (OEF), and oxygen consumption (MVO2) non-invasively in humans would provide new possibilities to understand cardiac physiology and different patho-physiological states. Methods: We developed and tested an optimized novel method to measure MBF, OEF, and MVO2 simultaneously both in the RV and LV free wall (FW) using positron emission tomography in healthy young men at rest and during supine bicycle exercise. Results: Resting MBF was not significantly different between the three myocardial regions. Exercise increased MBF in the LVFW and septum, but MBF was lower in the RV compared to septum and LVFW during exercise. Resting OEF was similar between the three different myocardial regions (~70%) and increased in response to exercise similarly in all regions. MVO2 increased approximately two to three times from rest to exercise in all myocardial regions, but was significantly lower in the RV during exercise as compared to septum LVFW. Conclusion: MBF, OEF, and MVO2 can be assessed simultaneously in the RV and LV myocardia at rest and during exercise. Although there are no major differences in the MBF and OEF between LV and RV myocardial regions in the resting myocardium, MVO2 per gram of myocardium appears to be lower the RV in the exercising healthy human heart due to lower mean blood flow. The presented method may provide valuable insights for the assessment of MBF, OEF and MVO2 in hearts in different pathophysiological states.

Positron emission tomography examination of cerebral blood flow and glucose metabolism in young CADASIL patients.

BACKGROUND AND PURPOSE: CADASIL causes repeated ischemic strokes leading to subcortical vascular dementia. The purpose of this study was to assess whether cerebral blood flow (CBF) and regional cerebral metabolic rates of glucose (rCMR(gluc)) in CADASIL patients are affected in early adulthood. METHODS: CBF and rCMR(gluc) were examined with positron emission tomography in correlation with magnetic resonance imaging (MRI) in 14 adult (19 to 41 years) CADASIL patients with the Notch3 R133C mutation. Seven patients had experienced transient ischemic attack and 3 had experienced > or =1 strokes. RESULTS: The mean CBF in the CADASIL patients was significantly lower in both frontal (P=0.019) and occipital (P=0.009) white matter (WM) than those in the controls. CBF decreased significantly with increased severity of the disease. The patients had lower mean rCMR(gluc) values than the controls, although differences were not statistically significant. Sum scores of semiquantitative MRI rating scale (Scheltens) correlated significantly with WM CBF but not with rCMR(gluc). CONCLUSIONS: In CADASIL, there is an early and significant decrease in the CBF of WM associated with simultaneous MRI changes. These are obviously caused by the arteriopathy in long penetrating arteries and indicate early tissue damage, also expressed as impaired rCMR(gluc) in the WM.

Ventilator add-on for delivering PET tracer gases.

OBJECTIVES: The increasing use of PET for assessing cerebral blood flow, oxygen metabolism, and blood volume in critically ill patients has created a need for reliable technical solutions for delivering (15)O-tracer gases to mechanically ventilated subjects. Our objective was to create such a solution. METHODS: We designed a ventilator add-on unit that enables complex functional brain studies using labeled oxygen and carbon monoxide gases as tracers. The unit manages both steady-state and bolus inhalations, and the latter can be manually initiated using a remote trigger. All parts conducting breathing gases can be sterilized. The unit can be operated during both spontaneous pressure support breathing and volume-controlled ventilation. It supports the standard safety features and alarms of the ventilator and includes an overflow valve in the bolus reservoir. RESULTS: The count rate curves obtained using the new unit were similar to those from the standard bag-inhalation method. CONCLUSION: The unit we describe offers an economical and easily operated solution for providing uninterrupted ventilator treatment while performing PET brain studies, and the provided treatment meets intensive care criteria.

Assessment of blood flow with (68)Ga-DOTA PET in experimental inflammation: a validation study using (15)O-water.

Increased blood flow and vascular permeability are key events in inflammation. Based on the fact that Gadolinium-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (Gd-DOTA) is commonly used in magnetic resonance (MR) imaging of blood flow (perfusion), we evaluated the feasibility of its Gallium-68 labeled DOTA analog ((68)Ga-DOTA) for positron emission tomography (PET) imaging of blood flow in experimental inflammation. Adult, male Sprague-Dawley rats with turpentine oil induced sterile skin/muscle inflammation were anesthetized with isoflurane, and imaged under rest and adenosine-induced hyperemia by means of dynamic 2-min Oxygen-15 labeled water (H2 (15)O) and 30-min (68)Ga-DOTA PET. For the quantification of PET data, regions of interest (ROIs) were defined in the focus of inflammation, healthy muscle, myocardium and heart left ventricle. Radioactivity concentration in the ROIs versus time after injection was determined for both tracers and blood flow was calculated using image-derived input. According to the H2 (15)O PET, blood flow was 0.69 ± 0.15 ml/min/g for inflammation and 0.15 ± 0.03 ml/min/g for muscle during rest. The blood flow remained unchanged during adenosine-induced hyperemia 0.67 ± 0.11 and 0.12 ± 0.03 ml/min/g for inflammation and muscle, respectively, indicating that adenosine has little effect on blood flow in peripheral tissues in rats. High focal uptake of (68)Ga-DOTA was seen at the site of inflammation throughout the 30-min PET imaging. According to the (68)Ga-DOTA PET, blood flow measured as the blood-to-tissue transport rate (K1) was 0.60 ± 0.07 ml/min/g for inflammation and 0.14 ± 0.06 ml/min/g for muscle during rest and 0.63 ± 0.08 ml/min/g for inflammation and 0.09 ± 0.04 ml/min/g for muscle during adenosine-induced hyperemia. The H2 (15)O-based blood flow and (68)Ga-DOTA-based K1 values correlated well (r = 0.94, P < 0.0001). These results show that (68)Ga-DOTA PET imaging is useful for the quantification of increased blood flow induced by inflammation.

Clinical value of absolute quantification of myocardial perfusion with (15)O-water in coronary artery disease.

BACKGROUND: The standard interpretation of perfusion imaging is based on the assessment of relative perfusion distribution. The limitations of that approach have been recognized in patients with multivessel disease and endothelial dysfunction. To date, however, no large clinical studies have investigated the value of measuring quantitative blood flow and compared that with relative uptake. METHODS AND RESULTS: One hundred four patients with moderate (30%-70%) pretest likelihood of coronary artery disease (CAD) underwent PET imaging during adenosine stress using (15)O-water and dynamic imaging. Absolute myocardial blood flow was calculated from which both standard relative myocardial perfusion images and images scaled to a known absolute scale were produced. The patients and the regions then were classified as normal or abnormal and compared against the reference of conventional angiography with fractional flow reserve. In patient-based analysis, the positive predictive value, negative predictive value, and accuracy of absolute perfusion in the detection of any obstructive CAD were 86%, 97%, and 92%, respectively, with absolute quantification. The corresponding values with relative analysis were 61%, 83%, and 73%, respectively. In region-based analysis, the receiver operating characteristic curves confirmed that the absolute quantification was superior to relative assessment. In particular, the specificity and positive predictive value were low using just relative differences in flow. Only 9 of 24 patients with 3-vessel disease were correctly assessed using relative analysis. CONCLUSIONS: The measurement of myocardial blood flow in absolute terms has a significant impact on the interpretation of myocardial perfusion. As expected, multivessel disease is more accurately detected.