Nicole Fettig - Academia.edu (original) (raw)

Papers by Nicole Fettig

Society of Nuclear Medicine Annual Meeting Abstracts, May 1, 2011

PLoS ONE, 2014

Estrogen exerts diverse biological effects in multiple tissues in both animals and humans. Much o... more Estrogen exerts diverse biological effects in multiple tissues in both animals and humans. Much of the accumulated knowledge on the role of estrogen receptor (ER) in the heart has been obtained from studies using ovariectomized mice, whole body ER gene knock-out animal models, ex vivo heart studies, or from isolated cardiac myocytes. In light of the wide systemic influence of ER signaling in regulating a host of biological functions in multiple tissues, it is difficult to infer the direct role of ER on the heart. Therefore, we developed a mouse model with a cardiomyocyte-specific deletion of the ERα allele (cs-ERα-/-). Male and female cs-ERα-/- mice with age/sex-matched wild type controls were examined for differences in cardiac structure and function by echocardiogram and differential gene expression microarray analysis. Our study revealed sex-differences in structural parameters in the hearts of cs-ERα-/- mice, with minimal functional differences. Analysis of microarray data revealed differential variations in the expression of 208 genes affecting multiple transcriptional networks. Furthermore, we report sex-specific differences in the expression of 56 genes. Overall, we developed a mouse model with cardiac-specific deletion of ERα to characterize the role of ERα in the heart independent of systemic effects. Our results suggest that ERα is involved in controlling the expression of diverse genes and networks in the cardiomyocyte in a sex-dependent manner.

Nuclear Medicine and Biology, 2013

Dietary conditions may affect liver [(18)F]FDG kinetics due to arterial and portal vein (PV) inpu... more Dietary conditions may affect liver [(18)F]FDG kinetics due to arterial and portal vein (PV) input. The purpose of this study was to evaluate kinetic models of [(18)F]FDG metabolism under a wide range of dietary interventions taking into account variations in arterial (HA) and portal vein (PV) input. The study consisted of three groups of rats maintained under different diet interventions: 12 h fasted, 24 h fasted and those fed with high fructose diet. [(15)O]H₂O PET imaging was used to characterize liver flow contribution from HA and PV to the liver&amp;amp;amp;amp;amp;amp;amp;#39;s dual input function (DIF). [(18)F]FDG PET imaging was used to characterize liver metabolism. Differences in [(18)F]FDG kinetics in HA, PV and liver under different diet interventions were investigated. An arterial to PV Transfer Function (TF) was optimized in all three dietary states to noninvasively estimate PV activity. Finally, two compartment 3-parameter (2C3P), two compartment 4-parameter (2C4P), two compartment 5-parameter (2C5P), and three compartment 5-parameter (3C5P) models were evaluated and compared to describe the kinetics of [(18)F]FDG in the liver across diet interventions. Sensitivity of the compartmental models to ratios of HA to PV flow fractions was further investigated. Differences were found in HA and PV [(18)F]FDG kinetics across 12h fasted, 24h fasted and high fructose fed diet interventions. A two exponential TF model was able to estimate portal activity in all the three diet interventions. Statistical analysis suggests that a 2C3P model configuration was adequate to describe the kinetics of [(18)F]FDG in the liver under wide ranging dietary interventions. The net influx of [(18)F]FDG was lowest in the 12h fasted group, followed by 24 h fasted group, and high fructose diet. A TF was optimized to non-invasively estimate PV time activity curve in different dietary states. Several kinetic models were assessed and a 2C3P model was sufficient to describe [(18)F]FDG liver kinetics despite differences in HA and PV kinetics across wide ranging dietary interventions. The observations have broader implications for the quantification of liver metabolism in metabolic disorders and cancer, among others.

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 17, 2014

Purpose: To investigate whether longitudinal functional PET imaging of mammary tumors using the r... more Purpose: To investigate whether longitudinal functional PET imaging of mammary tumors using the radiopharmaceuticals [18F]FDG (to measure glucose uptake), [18F]FES (to measure estrogen receptor (ER) levels), or [18F]FFNP (to measure progesterone receptor (PgR) levels) is predictive of response to estrogen deprivation therapy. Experimental Design: [18F]FDG, [18F]FES and [18F]FFNP uptake in endocrine-sensitive and -resistant mammary tumors was quantified serially by PET before ovariectomy or estrogen withdrawal in mice, and on days 3 and 4 after estrogen deprivation therapy. Specificity of [18F]FFNP uptake in ERα+ mammary tumors was determined by competition assay using unlabeled ligands for PgR or glucocorticoid receptor (GR). PgR expression was also assayed by immunohistochemistry (IHC). Results: The levels of [18F]FES and [18F]FDG tumor uptake remained unchanged in endocrine-sensitive tumors after estrogen deprivation therapy compared to those at pre-treatment. In contrast, estroge...

PLoS ONE, 2013

Lipotoxicity of the heart has been implicated as a leading cause of morbidity in Type 2 Diabetes ... more Lipotoxicity of the heart has been implicated as a leading cause of morbidity in Type 2 Diabetes Mellitus (T2DM). While numerous reports have demonstrated increased myocardial fatty acid (FA) utilization in obese T2DM animal models, this diabetic phenotype has yet to be demonstrated in non-obese animal models of T2DM. Therefore, the present study investigates functional, metabolic, and genomic differences in myocardial FA metabolism in non-obese type 2 diabetic rats. The study utilized Goto-Kakizaki (GK) rats at the age of 24 weeks. Each rat was imaged with small animal positron emission tomography (PET) to estimate myocardial blood flow (MBF) and myocardial FA metabolism. Echocardiograms (ECHOs) were performed to assess cardiac function. Levels of triglycerides (TG) and non-esterified fatty acids (NEFA) were measured in both plasma and cardiac tissues. Finally, expression profiles for 168 genes that have been implicated in diabetes and FA metabolism were measured using quantitative PCR (qPCR) arrays. GK rats exhibited increased NEFA and TG in both plasma and cardiac tissue. Quantitative PET imaging suggests that GK rats have increased FA metabolism. ECHO data indicates that GK rats have a significant increase in left ventricle mass index (LVMI) and decrease in peak early diastolic mitral annular velocity (E') compared to Wistar rats, suggesting structural remodeling and impaired diastolic function. Of the 84 genes in each the diabetes and FA metabolism arrays, 17 genes in the diabetes array and 41 genes in the FA metabolism array were significantly up-regulated in GK rats. Our data suggest that GK rats' exhibit increased genomic disposition to FA and TG metabolism independent of obesity.

Nuclear Medicine and Biology, 2008

Introduction-Progesterone receptors (PRs) are present in many breast tumors, and their levels are... more Introduction-Progesterone receptors (PRs) are present in many breast tumors, and their levels are increased by certain endocrine therapies. They can be used as targets for diagnostic imaging and radiotherapy.

Journal of Nuclear Medicine, 2012

Journal of Nuclear Medicine, 2008

Diabetic cardiomyopathy is associated with abnormalities in glucose metabolism. We evaluated myoc... more Diabetic cardiomyopathy is associated with abnormalities in glucose metabolism. We evaluated myocardial glucose metabolism in a rodent model of type 2 diabetes, namely the Zucker diabetic fatty (ZDF) rat, and validated PET measurements of glucose uptake against gene and protein expression of glucose transporters (GLUTs). Methods: Six lean and ZDF rats underwent small-animal PET at the age of 14 wk and at the age of 19 wk. The imaging protocol consisted of a 60-min dynamic acquisition with 18 F-FDG (18.5-29.6 MBq). Dynamic images were reconstructed using filtered backprojection with a 2.5 zoom on the heart and 40 frames per imaging session. PET measurements of myocardial glucose uptake (MGUp) rate and utilization were determined with an input function derived by the hybrid image-blood-sampling algorithm on recovery-corrected anterolateral myocardial regions of interest. After the PET session at week 19 (W19), hearts were extracted for gene and protein expression analysis of GLUT-1 and GLUT-4. The dependence of MGUp on gene expression of GLUT-1 and GLUT-4 was characterized by multiple-regression analysis. Results: MGUp in ZDF rats at both week 14 (W14) and W19 (P , 0.006) was significantly lower than MGUp in lean littermate control rats. Moreover, lean rats at W19 displayed significantly higher MGUp than they did at W14 (P 5 0.007). Consistent with a diminished MGUp result, gene expression of GLUT-4 was significantly (P 5 0.004) lower in ZDF rats. Finally, MGUp significantly (P 5 0.0003) correlated with gene expression of GLUT-4. Conclusion: Using small-animal PET, we confirmed alterations in myocardial glucose utilization and validated PET measurement of MGUp against gene and protein expression of GLUTs in the diabetic heart of an animal model of type 2 diabetes.

Circulation Research, 2005

Evidence is emerging that systemic metabolic disturbances contribute to cardiac myocyte dysfuncti... more Evidence is emerging that systemic metabolic disturbances contribute to cardiac myocyte dysfunction and clinically apparent heart failure, independent of associated coronary artery disease. To test the hypothesis that perturbation of lipid homeostasis in cardiomyocytes contributes to cardiac dysfunction, we engineered transgenic mice with cardiac-specific overexpression of fatty acid transport protein 1 (FATP1) using the ␣-myosin heavy chain gene promoter. Two independent transgenic lines demonstrate 4-fold increased myocardial free fatty acid (FFA) uptake that is consistent with the known function of FATP1. Increased FFA uptake in this model likely contributes to early cardiomyocyte FFA accumulation (2-fold increased) and subsequent increased cardiac FFA metabolism (2-fold). By 3 months of age, transgenic mice have echocardiographic evidence of impaired left ventricular filling and biatrial enlargement, but preserved systolic function. Doppler tissue imaging and hemodynamic studies confirm that these mice have predominantly diastolic dysfunction. Furthermore, ambulatory ECG monitoring reveals prolonged QT c intervals, reflecting reductions in the densities of repolarizing, voltage-gated K ϩ currents in ventricular myocytes. Our results show that in the absence of systemic metabolic disturbances, such as diabetes or hyperlipidemia, perturbation of cardiomyocyte lipid homeostasis leads to cardiac dysfunction with pathophysiological findings similar to those in diabetic cardiomyopathy. Moreover, the MHC-FATP model supports a role for FATPs in FFA import into the heart in vivo. (Circ Res. 2005;96:225-233.)

Academic Radiology, 2011

RATIONALE AND OBJECTIVES-Non-invasive longitudinal imaging of tumor vasculature could provide new... more RATIONALE AND OBJECTIVES-Non-invasive longitudinal imaging of tumor vasculature could provide new insights into the development of solid tumors, facilitating efficient delivery of therapeutics. In this study, we report three-dimensional imaging and characterization of tumor vascular architecture using a nanoparticle contrast agent and high-resolution computed tomography (CT) imaging.

Nuclear Medicine and Biology, 2005

Tracer kinetic modeling used in conjunction with positron emission tomography (PET) is an excelle... more 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. 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. 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. 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.