Biomedical subjects

Pilar Herrero

Publications and source records attributed to Pilar Herrero.

At least 19 recordsLinked to original sources

PubMed2006

Hxk2 regulates the phosphorylation state of Mig1 and therefore its nucleocytoplasmic distribution.

Mig1 and Hxk2 are two major mediators of glucose repression in Saccharomyces cerevisiae. However, the mechanism by which Hxk2 participates in the glucose repression signaling pathway is not completely understood. Recently, it has been demonstrated that Hxk2 interacts with Mig1 to generate a repressor complex located in the nucleus of S. cerevisiae. However, the mechanism by which Mig1 favors the presence of Hxk2 in the nucleus is not clear, and the function of Hxk2 at the nuclear repressor complex level is still unknown. Here, we report that serine 311 of Mig1 is a critical residue for interaction with Hxk2 and that this interaction is regulated by glucose. Our findings suggest that Snf1 interacts constitutively with the Hxk2 component of the repressor complex at high and low glucose conditions. Furthermore, we show that Snf1 binds to Mig1 under low glucose conditions and that binding is largely abolished after a shift to high glucose medium. We found that phosphorylation of serine 311 of Mig1 by Snf1 kinase is essential for Mig1 protein nuclear export and derepression of the SUC2 gene in glucose-limited cells. These results allow postulating that the Hxk2 operates by interacting both with Mig1 and Snf1 to inhibit the Mig1 phosphorylation at serine 311 during high glucose grown.

Active Transport, Cell Nucleus↗

PubMed2006

Increased myocardial fatty acid metabolism in patients with type 1 diabetes mellitus.

OBJECTIVES: The purpose of this study was to determine if myocardial fatty acid utilization (MFAU) and myocardial fatty acid oxidation (MFAO) are increased in diabetic patients. BACKGROUND: Experimental models of diabetes mellitus demonstrate that MFAU and MFAO are increased, and that this dependence on myocardial fatty acid metabolism may be detrimental to cardiac function. Whether similar metabolic changes occur in humans with diabetes mellitus is unclear. METHODS: Eleven healthy non-diabetic control patients (5 women, ages 25 +/- 5 years) and 11 otherwise healthy patients with type 1 diabetes mellitus (T1DM) (8 women, ages 36 +/- 10 years, HbA1c 8.4 +/- 1.9%) underwent positron emission tomography for the determination of myocardial blood flow (MBF); myocardial oxygen consumption (MVO2); myocardial glucose utilization (MGU); and MFAU, MFAO, and %MFAO. RESULTS: Plasma lactate, insulin, and MBF levels were similar between the two groups. However, plasma glucose (5.71 +/- 0.98 mumol/ml vs. 5.28 +/- 0.65 mumol/ml, p = 0.04), free fatty acid levels (0.60 +/- 0.24 mumol/ml vs. 0.19 +/- 0.07 mumol/ml, p < 0.0001), and MVO2 (6.64 +/- 2.21 vs. 4.51 +/- 1.39 mumol/g/min, p = 0.007) levels were higher in the T1DM subjects. Furthermore, compared with control patients, T1DM subjects exhibited higher MFAU (213 +/- 135 nmol/g/min vs. 57 +/- 28 nmol/g/min, p = 0.0004), MFAO (206 +/- 131 nmol/g/min s. 50 +/- 26 nmol/g/min, p = 0.0002), and %MFAO (94 +/- 6% vs. 81 +/- 19%, respectively, p = 0.04). In contrast, MGU was lower in T1DM subjects than in controls (207 +/- 108 nmol/g/min vs. 403 +/- 191 nmol/g/min, p = 0.0008). CONCLUSIONS: Humans with diabetes mellitus exhibit increased MFAU and MFAO and reduced MGU consistent with observations obtained in experimental models of diabetes.

Adult↗

PubMed2006

Minimally invasive method of determining blood input function from PET images in rodents.

UNLABELLED: For cardiovascular research on rodents, small-animal PET has limitations because of the inherent spatial resolution of the system and because of cardiac motion. A factor analysis (FA) technique for extracting the blood input function and myocardial time-activity curve from dynamic small-animal PET images of the rodent heart has been implemented to overcome these limitations. METHODS: Six Sprague-Dawley rats and 6 BALB/c mice underwent dynamic imaging with 18F-FDG (n = 6) and 1-11C-acetate (n = 6). From the dynamic images, blood input functions and myocardial time-activity curves were extracted by the FA method. The accuracy of input functions derived by the FA method was compared with that of input functions determined from serial blood samples, and the correlation coefficients were calculated. RESULTS: Factor images (right ventricle, left ventricle, and myocardium) were successfully extracted for both 18F-FDG and 1-11C-acetate in rats. The correlation coefficients for the input functions were 0.973 for 18F-FDG and 0.965 for 1-11C-acetate. In mice, the correlation coefficients for the input functions were 0.930 for 18F-FDG and 0.972 for 1-11C-acetate. CONCLUSION: The FA method enables minimally invasive extraction of accurate input functions and myocardial time-activity curves from dynamic microPET images of rodents without the need to draw regions of interest and without the possible complications of surgery and repeated blood sampling.

Animals↗

PubMed2006

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.

Acetates↗

PubMed2006

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.

Acetic Acid↗

PubMed2005

The effects of plasma insulin and glucose on myocardial blood flow in patients with type 1 diabetes mellitus.

OBJECTIVES: The objective of this study was to determine the impact of insulin and glucose on myocardial vasodilator function in patients with type 1 diabetes mellitus (T1DM). BACKGROUND: The relative importance of plasma insulin and glucose levels on the abnormal vasodilator function observed in T1DM is unknown. METHODS: Twenty T1DM patients underwent positron emission tomography studies to measure myocardial blood flow (MBF) (in ml/g/min) at rest (MBFr) and during adenosine (MBFa), both under baseline metabolic conditions and then during either hyperinsulinemic-euglycemic clamp (HE) (n = 10; 40 +/- 9 years, 8 female subjects, hemoglobin A1c [HbA1c] 7.8 +/- 1.1%) or hyperinsulinemic-hyperglycemic clamp (HH) (n = 10; 44 +/- 12 years, 8 female subjects, hemoglobin A1c 7.7 +/- 0.6%). RESULTS: Both groups showed similar MBFr and MBFa under baseline metabolic conditions (p = NS). Compared with baseline conditions, MBFr increased in the HH group (p < 0.005), whereas it did not change in the HE group. Compared with baseline conditions, MBFa decreased in the HH group (p < 0.05) but did not change in the HE group. Myocardial perfusion reserve (MPR) (MBFa/MBFr) was similar between the HE and HH groups at baseline (p = NS). During clamp, MPR tended to decrease in the HH group (p < 0.1) but did not change in the HE group (p = NS) when compared with baseline conditions. However, during the clamp MPR was significantly lower in the HH group when compared with the HE group (p < 0.0001). CONCLUSIONS: In the short term, hyperglycemia has a deleterious effect on myocardial vasodilator function, which outweighs the beneficial effect of hyperinsulinemia.

Adult↗

PubMed2005

Rgt1, a glucose sensing transcription factor, is required for transcriptional repression of the HXK2 gene in Saccharomyces cerevisiae.

Expression of HXK2, a gene encoding a Saccharomyces cerevisiae bifunctional protein with catalytic and regulatory functions, is controlled by glucose availability, being activated in the presence of glucose and inhibited when the levels of the sugar are low. In the present study, we identified Rgt1 as a transcription factor that, together with the Med8 protein, is essential for repression of the HXK2 gene in the absence of glucose. Rgt1 represses HXK2 expression by binding specifically to the motif (CGGAAAA) located at -395 bp relative to the ATG translation start codon in the HXK2 promoter. Disruption of the RGT1 gene causes an 18-fold increase in the level of HXK2 transcript in the absence of glucose. Rgt1 binds to the RGT1 element of HXK2 promoter in a glucose-dependent manner, and the repression of target gene depends on binding of Rgt1 to DNA. The physiological significance of the connection between two glucose-signalling pathways, the Snf3/Rgt2 that causes glucose induction and the Mig1/Hxk2 that causes glucose repression, was also analysed.

DNA-Binding Proteins↗

PubMed2005

Techniques necessary for multiple tracer quantitative small-animal imaging studies.

INTRODUCTION: An increasing number and variety of studies on rodent models are being conducted using small-animal positron emission tomography scanners. We aimed to determine if animal handling techniques could be developed to perform routine animal imaging in a timely and efficient manner and with minimal effect on animal physiology. These techniques need to be reproducible in the same animal while maintaining hemodynamic and physiological stability. METHODS: The necessary techniques include (a) the use of inhalant anesthesia, (b) arterial and venous cannulation for multiple tracer administrations and blood sampling, (c) development of small-volume analytic columns and techniques and (d) measurement of the physiological environment during the imaging session. RESULTS: We provide an example of a cardiac imaging study using four radiotracers (15O-water, 1-[11C]-acetate, 1-[11C]-palmitate and 1-[11C]-glucose) injected into normal rats. Plasma substrates, CO2 production and total metabolites were measured. The animals remained anesthetized over the entire imaging session, and their physiological state was maintained. CONCLUSION: The intrastudy stability of the physiological measurements and substrate levels and interstudy reproducibility of the measurements are reported.

Animals↗

PubMed2005

Measurement of input functions in rodents: challenges and solutions.

INTRODUCTION: Tracer kinetic modeling used in conjunction with positron emission tomography (PET) is an excellent tool for the noninvasive quantification of physiological, biological and molecular processes and their alterations due to disease. Currently, complex multi-compartment modeling approaches are being applied in a variety of clinical studies to determine myocardial perfusion, viability and glucose utilization as well as fatty acid metabolism and oxidation in the normal and diseased heart. These kinetic models require two key measurements of tracer activity over time, tracer activity in arterial blood (input function) and its corresponding activity in the organ of interest. The alteration in the time course of tracer activity as it travels from blood to the organ of interest describes the kinetics of the tracer. To be able to implement these approaches in rodent models of disease using small-animal PET (microPET), it is imperative that the input function is measured accurately. METHODS: The blood input functions in rodent experiments were obtained by (1) direct blood sampling, (2) direct measurement of blood activity by a beta-detecting probe that counts the activity in the blood, (3) an arterial-venous bypass (A/V shunt), (4) factor analysis of dynamic structures from dynamic PET images and (5) measurement from region-of-interest (ROI) analysis of dynamic PET images. Direct blood sampling was used as the reference standard to which the results of the other techniques were compared. RESULTS: Beta probes are difficult to operate and may not provide accurate blood input functions unless they are used intravenously, which requires complicated microsurgery. A similar limitation applies to the A/V shunt. Factor analysis successfully extracts the blood input function for mice and rats. The ROI-based method is less accurate due to limited image resolution of the PET system, which results in severe partial volume effect and spillover from myocardium. CONCLUSION: The current reference standard, direct blood sampling, is more invasive and has limited temporal resolution. With current imaging technology, image-based extraction of blood input functions is possible by factor analysis, while forthcoming technological developments are likely to allow extraction of input function directly from the images. These techniques will reduce the level of complexity and invasiveness for animal experiments and are likely to be used more widely in the future.

Animals↗

PubMed2004

A glucose response element from the S. cerevisiae hexose transporter HXT1 gene is sensitive to glucose in human fibroblasts.

Glucose is an essential nutrient, and a regulator of gene expression in eukaryotic cells. Here, a comparative, function-based genomic approach has been used to identify glucose regulatory elements and transduction pathways common to both yeast and mammalian cells. We have isolated a region in the promoter of the Saccharomyces cerevisiae hexose transporter gene HXT1 that conferred glucose sensitivity in yeast, when located upstream of the minimal CYC1 promoter. This element contained binding motifs for Rgt1, a transcriptional modulator involved in the yeast glucose-induction pathway, that were sufficient to elicit glucose responsiveness. The HXT1 regulatory element was then fused to the minimal cytomegalovirus promoter (HXT1-MIN) and inserted into an adenovirus for delivery to human fibroblasts, where it exhibited glucose-dependent transcriptional activation. Glucose action was mimicked by fructose and unrelated to glucose 6-P content, whilst non-metabolizable glucose analogues showed no effect. Activation of AMP kinase by 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranosanide blocked glucose induction, revealing parallels with the yeast glucose-repressing pathway. In contrast, delivery of Rgt1 to fibroblasts did not modify HXT1-MIN responsiveness. Thus, elements of the S.cerevisiae HXT1 gene conserve glucose regulation in human fibroblasts equivalent to the metabolism-dependent, glucose-repressing pathway in yeast. These data suggest that the instructions carried within gene regulatory elements controlling nutrient regulation of gene expression have been conserved throughout evolution.

Amino Acid Motifs↗

PubMed2004

Effect of obesity and insulin resistance on myocardial substrate metabolism and efficiency in young women.

BACKGROUND: Obesity is a risk factor for impaired cardiac performance, particularly in women. Animal studies suggest that alterations in myocardial fatty acid metabolism and efficiency in obesity can cause decreased cardiac performance. In the present study, we tested the hypothesis that myocardial fatty acid metabolism and efficiency are abnormal in obese women. METHODS AND RESULTS: We studied 31 young women (body mass index [BMI] 19 to 52 kg/m2); 19 were obese (BMI >30 kg/m2). Myocardial oxygen consumption (MVO2) and fatty acid uptake (MFAUp), utilization (MFAU), and oxidation (MFAO) were quantified by positron emission tomography. Cardiac work was measured by echocardiography, and efficiency was calculated as work/MVO2. BMI correlated with MVO2 (r=0.58, P=0.0006), MFAUp (r=0.42, P<0.05), and efficiency (r=-0.40, P<0.05). Insulin resistance, quantified by the glucose area under the curve (AUC) during an oral glucose tolerance test, correlated with MFAUp (r=0.55, P<0.005), MFAU (r=0.62, P<0.001), and MFAO (r=0.58, P<0.005). A multivariate, stepwise regression analysis showed that BMI was the only independent predictor of MVO2 and efficiency (P=0.0005 and P<0.05, respectively). Glucose AUC was the only independent predictor of MFAUp, MFAU, and MFAO (P<0.05, <0.005, and <0.005, respectively). CONCLUSIONS: In young women, obesity is a significant predictor of increased MVO2 and decreased efficiency, and insulin resistance is a robust predictor of MFAUp, MFAU, and MFAO. This increase in fatty acid metabolism and decrease in efficiency is concordant with observations made in experimental models of obesity. These metabolic changes may play a role in the pathogenesis of decreased cardiac performance in obese women.

Adult↗

PubMed2004

The glucose-regulated nuclear localization of hexokinase 2 in Saccharomyces cerevisiae is Mig1-dependent.

Two major mediators of glucose repression in Saccharomyces cerevisiae are the proteins Mig1 and Hxk2. The mechanism of Hxk2-dependent glucose repression pathway is not well understood, but the Mig1-dependent part of the pathway has been elucidated in great detail. Here we report that Hxk2 has a glucose-regulated nuclear localization and that Mig1, a transcriptional repressor responsible for glucose repression of many genes, is required to sequester Hxk2 into the nucleus. Mig1 and Hxk2 interacted in vivo in a yeast two-hybrid assay and in vitro in immunoprecipitation and glutathione S-transferase pull-down experiments. We found that the Lys(6)-Met(15) decapeptide of Hxk2, which is necessary for nuclear localization of the protein, is also essential for interaction with the Mig1 protein. Our results also show that the Hxk2-Mig1 interaction is of physiological significance because both proteins have been found interacting together in a cluster with DNA fragments containing the MIG1 site of SUC2 promoter. We conclude that Hxk2 operates by interacting with Mig1 to generate a repressor complex located in the nucleus of S. cerevisiae during growth in glucose medium.

Cell Nucleus↗

PubMed2004

Impact of reversible trapping of tracer and the presence of blood metabolites on measurements of myocardial glucose utilization performed by PET and 18F-fluorodeoxyglucose using the Patlak method.

In this study we demonstrated that significant egress of FDG from myocardium occurs within the first hour after tracer injection leading to nonlinear Patlak plots. There are also significant amounts of acidic FDG metabolites present in the blood. However, the impact of these metabolites on the estimates of myocardial glucose utilization (MGU) is negligible. Although further studies will be required to elucidate the reason for the egress of tracer from myocardium, not accounting for it will result in erroneous estimates of MGU.

Algorithms↗

PubMed2004

Imaging myocardium enzymatic pathways with carbon-11 radiotracers.

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Carbon Radioisotopes↗

PubMed2003

Impact of aging on myocardial metabolic response to dobutamine.

In humans, under resting conditions there is an age-related decrease in myocardial fatty acid utilization (MFAU) and oxidation (MFAO) and a relative increase in myocardial glucose utilization (MGU). The impact of age on an individual's myocardial metabolic response to catecholamines is not well defined. Sixteen younger (mean age, 26 +/- 5 yr) and 14 older (mean age, 69 +/- 4 yr) volunteers underwent positron emission tomography to measure myocardial blood flow, myocardial oxygen consumption (M.VO2), MFAU, MFAO, and MGU both under resting conditions and during dobutamine infusion. In response to dobutamine administration, the rate-pressure product, myocardial blood flow, and M.VO2 measurements increased by similar amounts in both groups. No age-related differences were noted in the responses of plasma insulin, glucose, fatty acid, or lactate levels to dobutamine. With dobutamine infusion, MFAU and MFAO increased by a similar extent in both younger and older volunteers (age/dobutamine interactions, P = 0.62 and 0.75, respectively). In contrast, MGU increased with dobutamine administration in the younger (from 149 +/- 71 to 209 +/- 78 nmol.g(-1).min(-1); P = 0.04) but not in the older (from 235 +/- 147 to 176 +/- 84 nmol.g(-1).min(-1); P = 0.23; age/dobutamine interaction, P = 0.03) group. With dobutamine infusion, hearts in both younger and older volunteers responded by increasing their MFAU and MFAO values. Whereas younger hearts also responded with an increase in MGU, older hearts did not. Although the clinical significance of these findings awaits further study, these results may partially explain the impaired contractile reserve and the increased incidence of cardiovascular disease in older individuals.

Adrenergic beta-Agonists↗

PubMed2003

Neurosecretory identity conferred by the apterous gene: lateral horn leucokinin neurons in Drosophila.

The LIM-HD protein Apterous has been shown to regulate expression of the FMRFamide neuropeptide in Drosophila neurons (Benveniste et al. [1998] Development 125:4757-4765). To test whether Apterous has a broader role in controlling neurosecretory identity, we analyzed the expression of several neuropeptides in apterous (ap) mutants. We show that Apterous is necessary for expression of the Leucokinin neuropeptide in a pair of brain neurons located in the lateral horn region of the protocerebrum (LHLK neurons). ap null mutants are depleted of Leucokinin in these cells, whereas hypomorphic mutants show reduced Leucokinin expression. Other Leucokinin-containing neurons are not affected by mutations in ap gene. Co-expression of apterous and Leucokinin is observed exclusively in the LHLK neurons, from larval stages to adulthood. Rescue assays performed in null ap mutants, by expressing Apterous protein under apGAL4 and elavGAL4 drivers, demonstrate the recovery of Leucokinin in the LHLK neurons. These results reinforce the emerging role of the LIM-HD proteins in determining neuronal identity. They also clarify the neuroendocrine phenotype of apterous mutants.

Animals↗

PubMed2003

Impact of aging on substrate metabolism by the human heart.

BACKGROUND: Results of studies in experimental animals have shown that, with age, myocardial fatty acid metabolism decreases, and glucose metabolism increases. Whether similar changes occur in humans is unknown. METHODS: Seventeen healthy younger normal volunteers (six males, 26 +/- 5 years) and 19 healthy older volunteers (nine males, 67 +/- 5 years) underwent positron emission tomography (PET) under resting conditions in the fasted state. Myocardial blood flow (MBF), myocardial oxygen consumption (MVO(2)), myocardial fatty acid utilization (MFAU) and oxidation (MFAO), and myocardial glucose utilization (MGU) were quantified by PET with (15)O-water, (11)C-acetate, (11)C-palmitate, and(11)C-glucose, respectively. RESULTS: Although MBF was similar between the groups, MVO(2) was higher in the older subjects (5.6 +/- 1.6 micromol/g/min) compared with younger subjects (4.6 +/- 1.0 micromol/g/min, p < 0.04). Rates of MFAU and MFAO (corrected for MVO(2)) were significantly lower in older subjects than in younger subjects (MFAU/MVO(2): 35 +/- 10 vs. 51 +/- 20 nmol free fatty acids (FFA)/nmol O(2) x 10(-3), p < 0.005, and MFAO/MVO(2): 33 +/- 10 vs. 48 +/- 18 nmol FFA/nmol O(2) x 10(-3), p < 0.004). In contrast, the rates of MGU corrected for MVO(2) did not differ between the groups. CONCLUSIONS: With aging, humans exhibit a decline in MFAU and MFAO. Although absolute rates of MGU do not increase, by virtue of the decline in MFAU there is likely an increase in relative contribution of MGU to substrate metabolism. The clinical significance of this metabolic switch awaits further study.

Adult↗

PubMed2003

Myocardial fatty acid metabolism: independent predictor of left ventricular mass in hypertensive heart disease.

The expression of myocardial fatty acid beta-oxidation enzymes is downregulated at the gene transcriptional level in animal models of left ventricular hypertrophy and of heart failure. Humans with idiopathic dilated cardiomyopathy have decreased myocardial fatty acid oxidation. The extent to which molecular mechanisms, such as a reduction in myocardial fatty acid oxidation, regulate the cardiac hypertrophic response in humans in vivo is unknown. Positron emission tomography was used to measure myocardial blood flow, oxygen consumption, fatty acid utilization, and oxidation in two groups of patients: (1) hypertensive left ventricular hypertrophy (n=19; left ventricular mass, 211+/-39 g; left ventricular ejection fraction, 67+/-4%) and (2) left ventricular dysfunction (n=9; left ventricular mass, 210+/-36 g; left ventricular ejection fraction, 31+/-10%); these were compared with a normal control group (n=36; left ventricular mass, 139+/-25 g; left ventricular ejection fraction, 66+/-6%). Left ventricular mass showed significant correlation with gender, diastolic and systolic blood pressure, myocardial fatty acid uptake, utilization and oxidation, myocardial blood flow, body mass index, and left ventricular ejection fraction (all P<0.02). Independent predictors of increased left ventricular mass were male gender (r=0.38, P<0.001), myocardial fatty acid oxidation (r=-0.24, P<0.018), systolic blood pressure (r=0.41, P<0.001), and left ventricular ejection fraction (r=-0.29, P=0.005). Thus, myocardial fatty acid metabolism is an independent predictor of left ventricular mass in hypertension and in left ventricular dysfunction. The extent to which reduced myocardial fatty acid metabolism affects cardiovascular morbidity and mortality and whether pharmacologic modulation results in improved outcomes remains to be determined.

Adult↗