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.

Breast feeding in infancy and arterial endothelial function later in life. The Cardiovascular Risk in Young Finns Study.

BACKGROUND/OBJECTIVES: Breast feeding in infancy may be associated with reduced cardiovascular morbidity in adulthood. We examined the association between breast feeding in infancy and arterial function and structure in adulthood in a population-based cohort of Finnish adults. SUBJECTS/METHODS: Noninvasive ultrasound was used to measure brachial artery flow-mediated dilatation (FMD), carotid artery intima-media thickness (IMT) and carotid artery compliance (CAC) in 1667 young adults participating in the Cardiovascular Risk in Young Finns Study with data on early nutrition. RESULTS: Maximal FMD was higher in breast-fed men compared to formula-fed men (7.2+/-4.0 vs 5.9+/-3.4%, P=0.029) while no differences were seen between breast-fed and formula-fed women (8.9+/-4.5 vs 8.8+/-5.0%, P=0.84). In men, the multivariable correlates of FMD included the group variable for breast feeding (P=0.014), birth weight (P=0.043), waist circumference (P<0.001) and baseline brachial artery diameter (P<0.001). In women, the multivariable correlates of FMD were birth weight (P=0.02), waist circumference (P<0.001) and brachial artery baseline diameter (P<0.001). Breast feeding was not significantly associated with IMT or CAC in multivariable models. CONCLUSIONS: Adult men who have been breast fed have better brachial endothelial function compared to men who have been formula fed.

Non-invasive estimation of hepatic blood perfusion from H2 15O PET images using tissue-derived arterial and portal input functions.

PURPOSE: The liver is perfused through the portal vein and the hepatic artery. When its perfusion is assessed using positron emission tomography (PET) and (15)O-labeled water (H(2) (15)O), calculations require a dual blood input function (DIF), i.e., arterial and portal blood activity curves. The former can be generally obtained invasively, but blood withdrawal from the portal vein is not feasible in humans. The aim of the present study was to develop a new technique to estimate quantitative liver perfusion from H(2) (15)O PET images with a completely non-invasive approach. METHODS: We studied normal pigs (n=14) in which arterial and portal blood tracer concentrations and Doppler ultrasonography flow rates were determined invasively to serve as reference measurements. Our technique consisted of using model DIF to create tissue model function and the latter method to simultaneously fit multiple liver time-activity curves from images. The parameters obtained reproduced the DIF. Simulation studies were performed to examine the magnitude of potential biases in the flow values and to optimize the extraction of multiple tissue curves from the image. RESULTS: The simulation showed that the error associated with assumed parameters was <10%, and the optimal number of tissue curves was between 10 and 20. The estimated DIFs were well reproduced against the measured ones. In addition, the calculated liver perfusion values were not different between the methods and showed a tight correlation (r=0.90). CONCLUSION: In conclusion, our results demonstrate that DIF can be estimated directly from tissue curves obtained through H(2) (15)O PET imaging. This suggests the possibility to enable completely non-invasive technique to assess liver perfusion in patho-physiological studies.

Myocardial and peripheral vascular functional adaptation to exercise training.

Exercise training seems to restore impaired vascular function in both peripheral and myocardial vessels in patients with coronary artery and peripheral vascular disease or in patients with risk factors for these diseases. However, the results on the effects of exercise training on vascular function in apparently healthy subjects are controversial. We studied the effects of long-term volitionally increased physical activity on peripheral and myocardial vascular function in nine young healthy male monozygotic twin pairs discordant for physical activity and fitness. The brothers were divided into more (MAG) and less active groups according to physical activity and fitness. The difference between groups in VO(2max) was 18+/-10% (P<0.001). Myocardial perfusion at rest, during adenosine-induced vasodilatation and during cold-pressor test and myocardial oxygen consumption were measured with positron emission tomography. In addition, endothelial function was measured using ultrasound in brachial and left anterior descending coronary arteries, and standard echocardiographic measures were taken. No differences were observed in myocardial perfusion measurements between groups. MAG tended to have a lower oxygen extraction fraction (P=0.06), but oxygen consumption was similar between the groups. No differences were found in coronary artery, myocardial resistance vessel or peripheral endothelial function between groups. These results suggest that when the effects of heredity are controlled, myocardial perfusion reserve and endothelial function, both in peripheral arteries and myocardial vessels, are not enhanced by increased physical activity and fitness in young healthy adult men.

Correlation of transthoracic Doppler echocardiography and magnetic resonance imaging in measuring left anterior descending artery flow velocity and time-course of dipyridamole-induced coronary flow increase.

There is an increasing need for new, functional and more quantitative parameters to assess coronary arterial function, for the purposes of evidence-based medicine. Coronary arterial function has been widely studied using pharmacological stimulation induced by dipyridamole or adenosine. Coronary flow reserve (CFR), defined as the ratio of pharmacologically induced hyperemic flow divided by basal flow, has been found to be an important functional index in both the clinical and subclinical stages of cardiovascular diseases. Ten healthy male volunteers were studied to compare transthoracic Doppler echocardiography (TTE) and MRI for measuring left anterior descending coronary artery (LAD) flow velocity and CFR. Additionally, the time-response curve of dipyridamole infusion was studied in five healthy males using TTE. Assessment of blood flow velocity, measured as MDV, PDV and VTI indicated Pearson's correlation coefficients of 0.88, 0.85 and 0.70, respectively, between flow velocity measurements performed using TTE and MRI. The results indicate that, despite minor differences in LAD diastolic velocities measured by TTE and MRI, the correlation of the LAD diastolic velocities measured using both methods are good and both methods are feasible for measuring CFR. Moreover, TTE has the unique capability of continuous measurement of LAD flow velocity, which allowed assessment of the time-response curve for dipyridamole-induced increase in LAD flow velocity in this study. This study indicates that the TTE method may be used in sequential or on-line monitoring of LAD blood flow velocity and therefore can be applied to evaluate the time- or dose-response effects of infused drugs in the coronary circulation of humans.

Population-based twin study of the effects of migration from Finland to Sweden on endothelial function and intima-media thickness.

Finnish men have higher coronary heart disease (CHD) mortality than Swedish men do. To assess the impact of migration to a country with lower CHD mortality on subclinical atherosclerosis, we measured early functional and structural atherosclerotic vascular changes in twins discordant for migration from Finland to Sweden. Conventional CHD risk factors, flow-mediated dilatation (FMD) of the brachial artery, carotid intima-media thickness, and carotid artery compliance were measured in 74 male twin pairs (20 monozygous, 54 dizygous), aged 42 to 69 years, in which co-one twin had migrated more than 20 years ago permanently to Sweden. There were no significant differences in CHD risk factors except for diastolic blood pressure and body fat percentage, which were higher in Sweden. In all subjects, mean FMD was non-significantly higher in Sweden (5.7+/-4.3% vs 4.9+/-4.2%, P=0.22), but in monozygous twins the difference in FMD was highly significant (7.2+/-4.4 vs 3.7+/-2.9%, P=0.003). There was no significant difference in intima-media thickness or carotid artery compliance between Sweden and Finland. We conclude that in Finnish monozygous twins the endothelial function is better among the twins that have migrated to a country with lower CHD prevalence.

Increased aortic intima-media thickness: a marker of preclinical atherosclerosis in high-risk children.

BACKGROUND: Autopsy studies in children have shown that atherosclerotic lesions begin to develop first in the intima of the aorta. Recent developments in ultrasound techniques have made it possible to visualize the intima-medial thickness of the abdominal aorta directly (aIMT). Therefore, we examined the feasibility of measuring aIMT in children and studied its value in distinguishing high-risk children from healthy controls compared with a more established marker of subclinical atherosclerosis, the common carotid artery intima-medial thickness (cIMT). METHODS AND RESULTS: IMTs were measured using high-resolution (13 MHz) ultrasound in 88 children (aged 11+/-2 years); 16 had hypercholesterolemia (LDL cholesterol, 5.1+/-1.2 mmol/L), 44 had type 1 diabetes (mean duration, 4.4+/-3.1 years; LDL cholesterol, 2.3+/-0.7 mmol/L), and 28 were healthy (controls; LDL cholesterol, 2.5+/-0.8 mmol/L). High-risk children had significantly increased aIMTs and cIMTs (both P<0.001) compared with controls. In controls, aIMT was similar to cIMT (P=NS), but aIMT was higher than cIMT in the children with hypercholesterolemia and diabetes (both P<0.01). Both markers showed excellent and approximately equal between-observer (<4%) and between-subject variation (<5%). CONCLUSIONS: Children with hypercholesterolemia and diabetes show increased IMTs compared with healthy controls, with a relatively greater increase in the aIMT than in the cIMT. Because atherosclerosis begins first in the intima of the aorta, these data suggest that the aIMT might provide the best currently available noninvasive marker of preclinical atherosclerosis in children.

Noninvasive assessment of brachial artery endothelial function with digital ultrasound and 13-MHz scanning frequency: feasibility of measuring the true inner luminal diameter using the intima-lumen interface.

Previous studies assessing endothelial function as flow-mediated changes in the brachial artery diameter have not been able to measure the true inner luminal diameter. This is due to the lack of image quality, which has hampered the visualisation of the lumen-intimal interface. Because increases in resolution and scanning frequency have recently led to improved ultrasound (US) image quality, we assessed the feasibility of measuring the true brachial artery diameter using digital US and 13-MHz scanning frequency. Satisfactory true inner diameter measurements were obtained in all subjects (n = 148, middle-aged men, mean age 54 +/- 7 y) participating in a risk factor study. At baseline flow, the intima to intima diameter was 4.03 +/- 0.49 and 4.67 +/- 0.52 mm measured conventionally from the anterior to the posterior media-adventitia interface (difference 0.64 +/- 0.10 mm). After hyperaemia, the intima to intima diameter was 4.23 +/- 0.46 mm and the adventitia to adventitia diameter 4.86 +/- 0.50 mm. Flow-mediated dilation (FMD) expressed as the percentage change from the baseline diameter measured 5.3 +/- 4.3% using the true inner diameters and 4.3 +/- 3.7% using the conventional outer diameters. The difference in FMD values was systematic, and there was a good linear correlation between them (r = 0.93, p < 0.0001). If FMD is presented as the percentage change from baseline to hyperaemia, this new method gives values that are approximately 1% unit higher, compared with values when brachial luminal diameter is measured in the conventional way between the adventitia-media interfaces.

HMG CoA reductase inhibitors are related to improved systemic endothelial function in coronary artery disease.

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase (statins) may enhance vascular endothelial function independent of their cholesterol lowering effect. To test this hypothesis, we surveyed two groups of patients (age 55+/-7, mean+/-SD) with coronary artery disease that were matched for age, blood pressure and serum lipid levels. Group 1 comprised 23 men without lipid-lowering medication and Group 2 included 22 patients with ongoing HMG CoA reductase inhibitor medication. Flow-mediated (endothelium-dependent) arterial dilatation (FMD) and nitrate-mediated (smooth muscle dependent) dilatation (NMD) were measured in the brachial artery using high resolution ultrasound. FMD was considerably higher in group 2 (4.3+/-2.6 vs. 2.6+/-2.8%; P<0.05). In multivariate regression model, statin use was the only significant (P<0.05) predictor of FMD. In all subjects, FMD correlated with statin dose (P<0.05 for trend). NMD was non-significantly higher in group 2 (11.4+/-5.0 vs. 9.0+/-4.2%, P=0. 08). We conclude that patients with established coronary artery disease on HMG CoA reductase inhibitor therapy have better vascular endothelial function than similar patients without the medication. These data provide further support for the idea that HMG CoA reductase inhibitors enhance endothelial function independent of their lipid-lowering effects. This may suggest that these drugs could be beneficial in secondary prevention of coronary artery disease regardless of the serum cholesterol concentration.