A primer in artificial intelligence in cardiovascular medicine.

Driven by recent developments in computational power, algorithms and web-based storage resources, machine learning (ML)-based artificial intelligence (AI) has quickly gained ground as the solution for many technological and societal challenges. AI education has become very popular and is oversubscribed at Dutch universities. Major investments were made in 2018 to develop and build the first AI-driven hospitals to improve patient care and reduce healthcare costs. AI has the potential to greatly enhance traditional statistical analyses in many domains and has been demonstrated to allow the discovery of 'hidden' information in highly complex datasets. As such, AI can also be of significant value in the diagnosis and treatment of cardiovascular disease, and the first applications of AI in the cardiovascular field are promising. However, many professionals in the cardiovascular field involved in patient care, education or science are unaware of the basics behind AI and the existing and expected applications in their field. In this review, we aim to introduce the broad cardiovascular community to the basics of modern ML-based AI and explain several of the commonly used algorithms. We also summarise their initial and future applications relevant to the cardiovascular field.

Automated SPECT analysis compared with expert visual scoring for the detection of FFR-defined coronary artery disease.

PURPOSE: Traditionally, interpretation of myocardial perfusion imaging (MPI) is based on visual assessment. Computer-based automated analysis might be a simple alternative obviating the need for extensive reading experience. Therefore, the aim of the present study was to compare the diagnostic performance of automated analysis with that of expert visual reading for the detection of obstructive coronary artery disease (CAD). METHODS: 206 Patients (64% men, age 58.2 ± 8.7 years) with suspected CAD were included prospectively. All patients underwent 99mTc-tetrofosmin single-photon emission computed tomography (SPECT) and invasive coronary angiography with fractional flow reserve (FFR) measurements. Non-corrected (NC) and attenuation-corrected (AC) SPECT images were analyzed both visually as well as automatically by commercially available SPECT software. Automated analysis comprised a segmental summed stress score (SSS), summed difference score (SDS), stress total perfusion deficit (S-TPD), and ischemic total perfusion deficit (I-TPD), representing the extent and severity of hypoperfused myocardium. Subsequently, software was optimized with an institutional normal database and thresholds. Diagnostic performances of automated and visual analysis were compared taking FFR as a reference. RESULTS: Sensitivity did not differ significantly between visual reading and most automated scoring parameters, except for SDS, which was significantly higher than visual assessment (p < 0.001). Specificity, however, was significantly higher for visual reading than for any of the automated scores (p < 0.001 for all). Diagnostic accuracy was significantly higher for visual scoring (77.2%) than for all NC images scores (p < 0.05), but not compared with SSS AC and S-TPD AC (69.8% and 71.2%, p = 0.063 and p = 0.134). After optimization of the automated software, diagnostic accuracies were similar for visual (73.8%) and automated analysis. Among the automated parameters, S-TPD AC showed the highest accuracy (73.5%). CONCLUSION: Automated analysis of myocardial perfusion SPECT can be as accurate as visual interpretation by an expert reader in detecting significant CAD defined by FFR.

Validation of [18F]fluorodeoxyglucose and positron emission tomography (PET) for the measurement of intestinal metabolism in pigs, and evidence of intestinal insulin resistance in patients with morbid obesity.

AIMS/HYPOTHESIS: The role of the intestine in the pathogenesis of metabolic diseases is gaining much attention. We therefore sought to validate, using an animal model, the use of positron emission tomography (PET) in the estimation of intestinal glucose uptake (GU), and thereafter to test whether intestinal insulin-stimulated GU is altered in morbidly obese compared with healthy human participants. METHODS: In the validation study, pigs were imaged using [(18)F]fluorodeoxyglucose ([(18)F]FDG) and the image-derived data were compared with corresponding ex vivo measurements in tissue samples and with arterial-venous differences in glucose and [(18)F]FDG levels. In the clinical study, GU was measured in different regions of the intestine in lean (n = 8) and morbidly obese (n = 8) humans at baseline and during euglycaemic hyperinsulinaemia. RESULTS: PET- and ex vivo-derived intestinal values were strongly correlated and most of the fluorine-18-derived radioactivity was accumulated in the mucosal layer of the gut wall. In the gut wall of pigs, insulin promoted GU as determined by PET, the arterial-venous balance or autoradiography. In lean human participants, insulin increased GU from the circulation in the duodenum (from 1.3 ± 0.6 to 3.1 ± 1.1 µmol [100 g](-1) min(-1), p < 0.05) and in the jejunum (from 1.1 ± 0.7 to 3.0 ± 1.5 µmol [100 g](-1) min(-1), p < 0.05). Obese participants failed to show any increase in insulin-stimulated GU compared with fasting values (NS). CONCLUSIONS/INTERPRETATION: Intestinal GU can be quantified in vivo by [(18)F]FDG PET. Intestinal insulin resistance occurs in obesity before the deterioration of systemic glucose tolerance.

Regional differences in blood flow, glucose uptake and fatty acid uptake within quadriceps femoris muscle during dynamic knee-extension exercise.

The purpose of the present study was to investigate the regional differences in glucose and fatty acid uptake within skeletal muscle during exercise. Blood flow (BF), glucose uptake (GU) and free fatty acid uptake (FFAU) were measured in four different regions (vastus lateralis, VL; rectus femoris, RF; vastus intermedius, VI; and vastus medialis, VM) of the quadriceps femoris (QF) muscle during low-intensity, knee-extension exercise using positron emission tomography. BF was higher in VI than in VL, RF and VM (P < 0.05). FFAU was higher in VI (P < 0.001) but also in VM (P < 0.05) compared with VL and RF. In contrast, GU was higher in RF compared with VL (P < 0.05) but was not significantly different to VM or VI (both P = NS). FFAU within these four muscle regions correlated significantly with BF (r = 0.951, P < 0.05), whereas no significant relationship was observed between GU and BF (r = 0.352, P = NS). Therefore, skeletal muscle FFAU, but not GU, appears to be associated with BF during low-intensity exercise. The present results also indicate considerable regional differences in substrate use within working QF muscle. As such, an important methodological outcome from these results is that one sample from a specific part of the QF muscle does not represent the response in the entire QF muscle group.

Similar patterns of myocardial metabolism and perfusion in patients with type 2 diabetes and heart disease of ischaemic and non-ischaemic origin.

AIMS/HYPOTHESIS: Type 2 diabetes and insulin resistance are often associated with the co-occurrence of coronary atherosclerosis and cardiac dysfunction. The aim of this study was to define the independent relationships between left ventricular dysfunction or ischaemia and patterns of myocardial perfusion and metabolism in type 2 diabetes. METHODS: Twenty-four type 2 diabetic patients--12 with coronary artery disease (CAD) and preserved left ventricular function and 12 with non-ischaemic heart failure (HF)--were enrolled in a cross-sectional study. Positron emission tomography (PET) was used to assess myocardial blood flow (MBF) at rest, after pharmacological stress and under euglycaemic hyperinsulinaemia. Insulin-mediated myocardial glucose disposal was determined with 2-deoxy-2-[(18)F]fluoroglucose PET. RESULTS: There was no difference in myocardial glucose uptake (MGU) between the healthy myocardium of CAD patients and the dysfunctional myocardium of HF patients. MGU was strongly influenced by levels of systemic insulin resistance in both groups (CAD, r = 0.85, p = 0.005; HF, r = 0.77, p = 0.01). In HF patients, there was an inverse association between MGU and the coronary flow reserve (r = -0.434, p = 0.0115). A similar relationship was observed in non-ischaemic segments of CAD patients. Hyperinsulinaemia increased MBF to a similar extent in the non-ischaemic myocardial of CAD and HF patients. CONCLUSIONS/INTERPRETATION: In type 2 diabetes, similar metabolic and perfusion patterns can be detected in the non-ischaemic regions of CAD patients with normal cardiac function and in the dysfunctional non-ischaemic myocardium of HF patients. This suggests that insulin resistance, rather than diagnosis of ischaemia or left ventricular dysfunction, affects the metabolism and perfusion features of patients with type 2 diabetes.

Cardiac positron emission tomography/computed tomography imaging accurately detects anatomically and functionally significant coronary artery disease.

BACKGROUND: Computed tomography (CT) is increasingly used to detect coronary artery disease, but the evaluation of stenoses is often uncertain. Perfusion imaging has an established role in detecting ischemia and guiding therapy. Hybrid positron emission tomography (PET)/CT allows combination angiography and perfusion imaging in short, quantitative, low-radiation-dose protocols. METHODS AND RESULTS: We enrolled 107 patients with an intermediate (30% to 70%) pretest likelihood of coronary artery disease. All patients underwent PET/CT (quantitative PET with (15)O-water and CT angiography), and the results were compared with the gold standard, invasive angiography, including measurement of fractional flow reserve when appropriate. Although PET and CT angiography alone both demonstrated 97% negative predictive value, CT angiography alone was suboptimal in assessing the severity of stenosis (positive predictive value, 81%). Perfusion imaging alone could not always separate microvascular disease from epicardial stenoses, but hybrid PET/CT significantly improved this accuracy to 98%. The radiation dose of the combined PET and CT protocols was 9.3 mSv (86 patients) with prospective triggering and 21.8 mSv (21 patients) with spiral CT. CONCLUSIONS: Cardiac hybrid PET/CT imaging allows accurate noninvasive detection of coronary artery disease in a symptomatic population. The method is feasible and can be performed routinely with <10 mSv in most patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00627172.

The effect of revascularization of atherosclerotic renal artery stenosis on coronary flow reserve and peripheral endothelial function.

BACKGROUND: Patients with atherosclerotic renovascular disease (ARVD) are at increased risk of heart disease because of associated hypertension, coronary artery disease, cardiac failure and chronic kidney disease. Although suggested to be beneficial, the cardiac effects of renal artery revascularization have not been well characterized. Our aim was to analyze the effects of percutaneous dilatation of renal artery stenosis (RAS) in ARVD patients on coronary and peripheral vascular function. METHODS: Nineteen ARVD patients [11 females and 8 males, age at study entry (mean ± SD) 69 ± 10 years] were treated by dilatation of unilateral (n = 9) or bilateral (n = 10) RAS, mainly because of uncontrolled or refractory hypertension. The patients were studied before and after the procedure (103 ± 29 days). They underwent echocardiography and peripheral artery endothelial function testing using flow-mediated dilatation (FMD) of brachial artery at rest and during reactive hyperemia. Myocardial blood flow was measured using quantitative PET perfusion imaging at baseline and during dipyridamole-induced hyperemia. RESULTS: Peripheral endothelial function, tested by FMD, as well as systolic blood pressure and left ventricular mass were improved in patients with bilateral RAS. However, myocardial perfusion and coronary flow reserve (CFR) did not change after the RAS dilatation. CONCLUSION: This is the first study to analyze the stage of myocardial perfusion and CFR in ARVD patients. Although peripheral endothelial function, systolic blood pressure and left ventricular hypertrophy were improved in patients with bilateral RAS by revascularization of RAS, it did not have any effect on coronary perfusion.

Estimation of optimal number of gates in dual gated 18F-FDG cardiac PET.

Gating of positron emission tomography images has been shown to reduce the motion effects, especially when imaging small targets, such as coronary plaques. However, the selection of optimal number of gates for gating remains a challenge. Selecting too high number of gates results in a loss of signal-to-noise ratio, while too low number of gates does remove only part of the motion. Here, we introduce a respiratory-cardiac motion model to determine the optimal number of respiratory and cardiac gates. We evaluate the model using a realistic heart phantom and data from 12 cardiac patients (47-77 years, 64.5 on average). To demonstrate the benefits of our model, we compared it with an existing respiratory model. Based on our study, the optimal number of gates was determined to be five respiratory and four cardiac gates in the phantom and patient studies. In the phantom study, the diameter of the most active hot spot was reduced by 24% in the dual gated images compared to non-gated images. In the patient study, the thickness of myocardium wall was reduced on average by 21%. In conclusion, the motion model can be used for estimating the optimal number of respiratory and cardiac gates for dual gating.

Impact of scan quality on the diagnostic performance of CCTA, SPECT, and PET for diagnosing myocardial ischemia defined by fractional flow reserve.

BACKGROUND: Scan quality can have a significant effect on the diagnostic performance of non-invasive imaging techniques. However, the extent of its influence has scarcely been investigated in a head-to-head manner. METHODS: Two-hundred and eight patients underwent CCTA, SPECT, and PET prior to invasive fractional flow reserve measurements. Scan quality was classified as either good, moderate, or poor. RESULTS: Distribution of good, moderate, and poor quality scans was; CCTA; 66%, 22%, 13%; SPECT; 52%, 38%, 9%; PET; 86%, 13%, 1%. Good quality CCTA scans possessed a higher specificity (75% vs. 31%, p = 0.001), positive predictive value (PPV, 71% vs. 51%, p = 0.050), and accuracy (80% vs. 60%, p = 0.009) compared to moderate quality scans, while sensitivity (94%) and negative predictive value (NPV, 88%) were similar to moderate and poor quality scans. Sensitivity (76%), NPV (84%), and accuracy (85%) of good quality SPECT scans was superior to those of moderate (41% p = 0.001, 56% p = 0.010, 70% p = 0.010) and poor quality (30% p = 0.003, 65% p = 0.069, 63% p = 0.038). Specificity (92%) and PPV (87%) of good quality SPECT scans did not differ from scans of diminished quality. Good quality PET scans exhibited high sensitivity (84%), specificity (86%), NPV (88%), PPV (81%) and accuracy (85%), which was comparable to scans of lesser quality. Good quality CCTA, SPECT, and PET scans demonstrated a similar diagnostic accuracy (p = 0.247). CONCLUSION: Diagnostic performance of CCTA, and SPECT is hampered by scan quality, while the diagnostic value of PET is not affected. Good quality CCTA, SPECT, and PET scans possess a high diagnostic accuracy.

Non-invasive estimation of hepatic glucose uptake from [18F]FDG PET images using tissue-derived input functions.

PURPOSE: The liver is perfused through the portal vein and hepatic artery. Quantification of hepatic glucose uptake (HGU) using PET requires the use of an input function for both the hepatic artery and portal vein. The former can be generally obtained invasively, but blood withdrawal from the portal vein is not practical in humans. The aim of this study was to develop and validate a new technique to obtain quantitative HGU by estimating the input function from PET images. METHODS: Normal pigs (n = 12) were studied with [18F]FDG PET, in which arterial and portal blood time-activity curves (TAC) were determined invasively to serve as reference measurements. The present technique consisted of two characteristics, i.e. using a model input function and simultaneously fitting multiple liver tissue TACs from images by minimizing the residual sum of square between the tissue TACs and fitted curves. The input function was obtained from the parameters determined from the fitting. The HGU values were computed by the estimated and measured input functions and compared between the methods. RESULTS: The estimated input functions were well reproduced. The HGU values, ranging from 0.005 to 0.02 ml/min per ml, were not significantly different between the two methods (r = 0.95, p < 0.001). A Bland-Altman plot demonstrated a small overestimation by the image-derived method with a bias of 0.00052 ml/min per g for HGU. CONCLUSION: The results presented demonstrate that the input function can be estimated directly from the PET image, supporting the fully non-invasive assessment of liver glucose metabolism in human studies.

NEMA NU 4-2008 and in vivo imaging performance of RAYCAN trans-PET/CT X5 small animal imaging system.

The RAYCAN Trans-PET/CT X5 is a preclinical positron emission tomography and computed tomography (PET/CT) system intended for in vivo imaging of rats and mice, featuring all-digital readout electronics for PET data acquisition. The National Electrical Manufacturers Association (NEMA) NU 4-2008 performance evaluation was conducted on the RAYCAN Trans-PET/CT X5 in addition to assessing in vivo imaging performance of the system on live animals. The performance characteristics of the system were evaluated, including system spatial resolution, count rate performance, sensitivity and image quality. The system imaging performance is assessed in dynamic in vivo PET imaging. The system resolution defined as full width half maximum (FWHM) was 2.07 mm, 2.11 mm and 1.31 mm for the tangential, radial and axial resolution, respectively, at the center of the field of view. The peak noise equivalent count rate (NECR) values measured were 61 kcps at 0.19 MBq ml-1 for the rat size phantom and 126 kcps at 1.53 MBq ml-1 for the mouse size phantom. Scatter fractions were 24% and 14% for the rat and mouse phantom. The measured peak sensitivity of the system was 1.70%. Image quality in static imaging was deemed sufficient based on the image quality phantom study, with average activity concentration of 155 ± 8.6 kBq ml-1 and image uniformity of 5.57% when using two-dimensional filtered backprojection algorithm (2D-FBP). Rods in the image quality phantom were visualized easily up to 2 mm in size. In dynamic in vivo PET imaging, time-activity-curves from several regions were successfully measured, characterizing the radioactivity distribution in myocardial blood pool, liver, left ventricle and the lung. In conclusion, the RAYCAN Trans-PET/CT X5 system can be considered a suitable option for basic imaging needs in preclinical imaging.

Data on the impact of scan quality on the diagnostic performance of CCTA, SPECT, and PET for diagnosing myocardial ischemia defined by fractional flow reserve on a per vessel level.

Scan quality directly impacts the diagnostic performance of non-invasive imaging modalities as reported in a substudy of the PACIFC-trial: "Impact of Scan Quality on the Diagnostic Performance of CCTA, SPECT, and PET for Diagnosing Myocardial Ischemia Defined by Fractional Flow Reserve" [1]. This Data-in-Brief paper supplements the hereinabove mentioned article by presenting the diagnostic performance of CCTA, SPECT, and PET on a per vessel level for the detection of hemodynamic significant coronary artery disease (CAD) when stratified according to scan quality and vascular territory.

The association of coronary lumen volume to left ventricle mass ratio with myocardial blood flow and fractional flow reserve.

BACKGROUND: A diminished coronary lumen volume to left ventricle mass ratio (V/M) derived from coronary computed tomography angiography (CCTA) has been proposed as factor contributing to impaired myocardial blood flow (MBF) even in the absence of obstructive disease on invasive coronary angiography (ICA). METHODS: Patients underwent CCTA, and positron emission tomography (PET) prior to ICA. Matched global V/M, global, and vessel specific hyperaemic MBF (hMBF), coronary flow reserve (CFR), and, FFR were available for 431 vessels in 152 patients. The median V/M (20.71 mm3/g) was used to divide the population into patients with either a low V/M or a high V/M. RESULTS: Overall, a higher percentage of vessels with an abnormal hMBF and FFR (34% vs. 19%, p = 0.009 and 20% vs. 9%, p = 0.004), as well as a lower FFR (0.93 [interquartile range: 0.85-0.97] vs. 0.95 [0.89-0.98], p = 0.016) values were observed in the low V/M group. V/M was weakly associated with vessel specific hMBF (R = 0.148, p = 0.027), and FFR (R = 0.156, p < 0.001). Among vessels with non-obstructive CAD on ICA (361 vessels), no association between V/M and vessel specific hMBF nor CFR was noted. However, in the absence of obstructive CAD, V/M was associated with (R = 0.081, p = 0.027), and independently predictive for FFR (p = 0.047). CONCLUSION: Overall, an abnormal vessel specific hMBF and FFR were more prevalent in patients with a low V/M compared to those with a high V/M. Furthermore, V/M was weakly associated with vessel specific hMBF and FFR. In the absence of obstructive CAD on ICA, V/M was weakly associated with notwithstanding independently predictive for FFR.

Amino-acid-based peritoneal dialysis solution improves amino-acid transport into skeletal muscle.

Abnormalities of amino-acid (AA) and protein metabolism are known to occur in chronic kidney disease (CKD). Protein malnutrition may contribute to impaired prognosis of dialysis patients. A crucial step in protein metabolism is AA transport into the cells. We compared the effects of an AA-containing peritoneal dialysis (PD) solution to glucose-based solutions on skeletal muscle AA uptake. Thirteen nondiabetic PD patients were studied twice in a random order and in a crossover manner both in the fasting state and during euglycemic insulin stimulation using [(11)C]methylaminoisobutyrate ([(11)C]MeAIB) and positron emission tomography (PET). Before both PET study days, patients had been using either glucose-based PD solutions only or one daily bag of AA solution in addition to glucose-based PD solutions for at least 6 weeks. Skeletal muscle AA uptake was calculated with graphical analysis. AA-containing PD solution increased plasma AA concentrations from 2.18+/-0.34 to 3.08+/-0.55 mmol l(-1) in the fasting state (P=0.0002) and from 1.88+/-0.15 to 2.42+/-0.30 mmol l(-1) during insulin stimulation (P<0.0001). As compared to PD treatment using glucose-based solutions only, skeletal muscle AA uptake was significantly higher during treatment containing AA solution both in the fasting state (15.2+/-5.8 vs 20.0+/-5.6 micromol kg(-1) min(-1), respectively, P=0.0057) and during insulin stimulation (16.8+/-4.5 vs 21.1+/-4.9 micromol kg(-1) min(-1), respectively, P=0.0046). In conclusion, PD treatment with an AA-containing PD solution is associated with a significant increase in skeletal muscle AA uptake both in the fasting state and during insulin stimulation.

Twenty-four-month alpha-galactosidase A replacement therapy in Fabry disease has only minimal effects on symptoms and cardiovascular parameters.

Fabry disease is an X-linked lysosomal storage disease caused by deficiency of alpha-galactosidase A enzyme activity. Decreased enzyme activity leads to accumulation of glycosphingolipids in different tissues including endothelial cells and smooth-muscle cells and cardiomyocytes, and cardiovascular complications are common in the disease. Since 2001, specific enzyme replacement therapy (ERT) with alpha-galactosidase A has been available. It has been reported to improve clinical symptoms and quality of life. However, limited and controversial data on its efficacy to cardiac involvement have been published. Nine patients (5 male) with Fabry disease were included in an open-label prospective follow-up study of 24-month ERT. Comprehensive cardiovascular evaluation was performed by MRI, stress echocardiography and quality of life assessment. Plasma globotriaosylceramide decreased from 6.2 to 1.4 microg/ml during ERT (p<0.05). The only other measured parameters that changed significantly were resting heart rate that decreased from 79 to 67 bpm (p<0.01) and end-systolic volume that decreased by 12.4 ml (p<0.05). The other parameters consisting of quality of life, self-estimated cardiovascular condition, diastolic function, exercise capacity, ECG parameters, ejection fraction and ventricular mass did not change. ERT has only minimal effect on symptoms and cardiovascular morphology and function in Fabry disease. Therefore, effective conventional medical therapy is still of major importance in Fabry disease. Larger ERT studies are warranted, especially in women, to solve current open questions, such as the age at which ERT should be started, optimal dosage and intervals between infusions. Furthermore, longer follow-up studies are needed to assess the effects of ERT on prognosis.

Insulin resistance of glucose uptake in skeletal muscle cannot be ameliorated by enhancing endothelium-dependent blood flow in obesity.

We tested the hypothesis that endothelium-dependent vasodilatation is a determinant of insulin resistance of skeletal muscle glucose uptake in human obesity. Eight obese (age 26+/-1 yr, body mass index 37+/-1 kg/m2) and seven nonobese males (25+/-2 yr, 23+/-1 kg/m2) received an infusion of bradykinin into the femoral artery of one leg under intravenously maintained normoglycemic hyperinsulinemic conditions. Blood flow was measured simultaneously in the bradykinin and insulin- and the insulin-infused leg before and during hyperinsulinemia using [15O]-labeled water ([15O]H2O) and positron emission tomography (PET). Glucose uptake was quantitated immediately thereafter in both legs using [18F]- fluoro-deoxy-glucose ([18F]FDG) and PET. Whole body insulin-stimulated glucose uptake was lower in the obese (507+/-47 mumol/m2 . min) than the nonobese (1205+/-97 micromol/m2 . min, P < 0.001) subjects. Muscle glucose uptake in the insulin-infused leg was 66% lower in the obese (19+/-4 micromol/kg muscle . min) than in the nonobese (56+/-9 micromol/kg muscle . min, P < 0.005) subjects. Bradykinin increased blood flow during hyperinsulinemia in the obese subjects by 75% from 16+/-1 to 28+/-4 ml/kg muscle . min (P < 0.05), and in the normal subjects by 65% from 23+/-3 to 38+/-9 ml/kg muscle . min (P < 0.05). However, this flow increase required twice as much bradykinin in the obese (51+/-3 microg over 100 min) than in the normal (25+/-1 mug, P < 0.001) subjects. In the obese subjects, blood flow in the bradykinin and insulin-infused leg (28+/-4 ml/kg muscle . min) was comparable to that in the insulin-infused leg in the normal subjects during hyperinsulinemia (24+/-5 ml/kg muscle . min). Despite this, insulin-stimulated glucose uptake remained unchanged in the bradykinin and insulin-infused leg (18+/-4 mumol/kg . min) compared with the insulin-infused leg (19+/-4 micromol/kg muscle . min) in the obese subjects. Insulin-stimulated glucose uptake also was unaffected by bradykinin in the normal subjects (58+/-10 vs. 56+/-9 micromol/kg . min, bradykinin and insulin versus insulin leg). These data demonstrate that obesity is characterized by two distinct defects in skeletal muscle: insulin resistance of cellular glucose extraction and impaired endothelium-dependent vasodilatation. Since a 75% increase in blood flow does not alter glucose uptake, insulin resistance in obesity cannot be overcome by normalizing muscle blood flow.

Glucose-free fatty acid cycle operates in human heart and skeletal muscle in vivo.

Positron emission tomography permits noninvasive measurement of regional glucose uptake in vivo in humans. We employed this technique to determine the effect of FFA on glucose uptake in leg, arm, and heart muscles. Six normal men were studied twice under euglycemic hyperinsulinemic (serum insulin approximately 500 pmol/liter) conditions, once during elevation of serum FFA by infusions of heparin and Intralipid (serum FFA 2.0 +/- 0.4 mmol/liter), and once during infusion of saline (serum FFA 0.1 +/- 0.01 mmol/liter). Regional glucose uptake rates were measured using positron emission tomography-derived 18F-fluoro-2-deoxy-D-glucose kinetics and the three-compartment model described by Sokoloff (Sokoloff, L., M. Reivich, C. Kennedy, M. C. Des Rosiers, C. S. Patlak, K. D. Pettigrew, O. Sakurada, and M. Shinohara. 1977. J. Neurochem. 28: 897-916). Elevation of plasma FFA decreased whole body glucose uptake by 31 +/- 2% (1,960 +/- 130 vs. 2,860 +/- 250 mumol/min, P less than 0.01, FFA vs. saline study). This decrease was due to inhibition of glucose uptake in the heart by 30 +/- 8% (150 +/- 33 vs. 200 +/- 28 mumol/min, P less than 0.02), and in skeletal muscles; both when measured in femoral (1,594 +/- 261 vs. 2,272 +/- 328 mumol/min, 25 +/- 13%) and arm muscles (1,617 +/- 411 to 2,305 +/- 517 mumol/min, P less than 0.02, 31 +/- 6%). Whole body glucose uptake correlated with glucose uptake in femoral (r = 0.75, P less than 0.005), and arm muscles (r = 0.69, P less than 0.05) but not with glucose uptake in the heart (r = 0.04, NS). These data demonstrate that the glucose-FFA cycle operates in vivo in both heart and skeletal muscles in humans.

Role of blood flow in regulating insulin-stimulated glucose uptake in humans. Studies using bradykinin, [15O]water, and [18F]fluoro-deoxy-glucose and positron emission tomography.

Defects in insulin stimulation of blood flow have been used suggested to contribute to insulin resistance. To directly test whether glucose uptake can be altered by changing blood flow, we infused bradykinin (27 microgram over 100 min), an endothelium-dependent vasodilator, into the femoral artery of 12 normal subjects (age 25+/-1 yr, body mass index 22+/-1 kg/m2) after an overnight fast (n = 5) and during normoglycemic hyperinsulinemic (n = 7) conditions (serum insulin 465+/-11 pmol/liter, 0-100 min). Blood flow was measured simultaneously in both femoral regions using [15O]-labeled water ([15O]H2O) and positron emission tomography (PET), before and during (50 min) the bradykinin infusion. Glucose uptake was measured immediately after the blood flow measurement simultaneously in both femoral regions using [18F]-fluoro-deoxy-glucose ([18F]FDG) and PET. During hyperinsulinemia, muscle blood flow was 58% higher in the bradykinin-infused (38+/-9 ml/kg muscle x min) than in the control leg (24+/-5, P<0.01). Femoral muscle glucose uptake was identical in both legs (60.6+/-9.5 vs. 58.7+/-9.0 micromol/kg x min, bradykinin-infused vs control leg, NS). Glucose extraction by skeletal muscle was 44% higher in the control (2.6+/-0.2 mmol/liter) than the bradykinin-infused leg (1.8+/-0.2 mmol/liter, P<0.01). When bradykinin was infused in the basal state, flow was 98% higher in the bradykinin-infused (58+/-12 ml/kg muscle x min) than the control leg (28+/-6 ml/kg muscle x min, P<0.01) but rates of muscle glucose uptake were identical in both legs (10.1+/-0.9 vs. 10.6+/-0.8 micromol/kg x min). We conclude that bradykinin increases skeletal muscle blood flow but not muscle glucose uptake in vivo. These data provide direct evidence against the hypothesis that blood flow is an independent regulator of insulin-stimulated glucose uptake in humans.

Exercise restores skeletal muscle glucose delivery but not insulin-mediated glucose transport and phosphorylation in obese subjects.

CONTEXT/OBJECTIVE: Insulin resistance in obese subjects results in the impaired disposal of glucose by skeletal muscle. The current study examined the effects of insulin and/or exercise on glucose transport and phosphorylation in skeletal muscle and the influence of obesity on these processes. SUBJECTS/METHODS: Seven obese and 12 lean men underwent positron emission tomography with 2-deoxy-2-[(18)F]fluoro-d-glucose in resting and isometrically exercising skeletal muscle during normoglycemic hyperinsulinemia. Data were analyzed by two-tissue compartmental modeling. Perfusion and oxidative capacity were measured during insulin stimulation by [15O]H2O and [15O]O2. RESULTS: Exercise increased glucose fractional uptake (K), inward transport rate (K(1)), and the k(3) parameter, combining transport and intracellular phosphorylation, in lean and obese subjects. In each group, there was no statistically significant difference between plasma flow and K(1). At rest, a significant defect in K(1) (P = 0.0016), k(3) (P = 0.016), and K (P = 0.022) was found in obese subjects. Exercise restored K(1), improved but did not normalize K (P = 0.03 vs. lean), and did not ameliorate the more than 60% relative impairment in k(3) in obese individuals (P = 0.002 vs. lean). The glucose oxidative potential tended to be reduced by obesity. CONCLUSIONS/INTERPRETATION: The study indicates that exercise restores the impairment in insulin-mediated skeletal muscle perfusion and glucose delivery associated with obesity but does not normalize the defect involving the proximal steps regulating glucose disposal in obese individuals. Our data support the use of 2-deoxy-2-[18F]fluoro-d-glucose-positron emission tomography in the dissection between substrate supply and intrinsic tissue metabolism.