Quantitative PET Imaging Detects Early Metabolic Remodeling in a Mouse Model of Pressure-Overload Left Ventricular Hypertrophy In Vivo

Abstract

We proposed that metabolic remodeling in the form of increased myocardial glucose analogue 2-[18F] fluoro-2deoxy-D-glucose (FDG) uptake precedes and triggers the onset of severe contractile dysfunction in pressure overload left ventricular hypertrophy (LVH) in vivo. To test this hypothesis we used a mouse model of transverse aortic constriction (TAC) together with Positron Emission Tomography (PET) and assessed serial changes in cardiac metabolism and function over 7 days. Methods PET scans of 16 C57BL/6 male mice were performed using a microPET scanner under sevofluorane anesthesia. A 10-minute transmission scan was followed by a 60-minute dynamic FDG-PET scan with cardiac and respiratory gating. Blood glucose levels were measured before and after the emission scan. Transverse aortic constriction (TAC) and sham surgeries were performed after baseline imaging. Osmotic mini-pumps containing either propranolol (5 mg/kg/day) or vehicle alone were implanted subcutaneously at the end of surgery. Subsequent scans were taken at days 1 and 7 after surgery. A compartment model, in which the blood input function with spill-over and partial volume corrections and the metabolic rate constants in a 3-compartment model are simultaneously estimated, was used to determine the net myocardial FDG influx constant, Ki. The rate of myocardial glucose use, rMGU, was also computed. Estimations of the ejection fractions (EF) were based on the high resolution gated PET images Results Mice undergoing TAC surgery exhibited an increase in the Ki (580%) and glucose usage the day after surgery indicating early adaptive response. On day 7 the EF had decreased by 24% indicating a maladaptive response. Average Ki increases were not linearly associated with increases in rMGU. Ki exceeded rMGU by 29% in the TAC mice. TAC Mice treated with propranolol attenuated rate of FDG uptake, diminished mismatch between Ki and rMGU (9%) and rescued cardiac function. Conclusions Metabolic maladaptation precedes the onset of severe contractile dysfunction. Both are prevented by treatment with propranolol. Early detection of metabolic remodeling may offer a metabolic target for modulation of hypertrophy.

Quantitative Dynamic PET Imaging of the Heart: From Mouse to Man

“…Metabolic remodeling preceded the development of LVH [2]. The LVH population exhibited higher septal wall thickness and heart weight to body weight ratios compared to [82], where data acquisition was initiated a few seconds before the slow administration of about 800 µCi 13 N-amonia over 30 seconds via the catheter.…”

“…Using this method we tested the hypothesis in mice heart in vivo, that early metabolic remodeling in the form of increased myocardial FDG uptake precedes structural LV remodeling in conjunction with a decrease in cardiac function, in an acute mouse model of transverse aortic constriction (TAC) induced pressure overload LVH [2] [87]. The TAC mouse model [79][136] lacks some of the key features of the human disease, most importantly the slow progressive development of pressure overload.…”

“…In chapter 4 and 5 we developed an improved methodology for non-invasive quantification of rate of myocardial glucose uptake in vivo in the mouse heart using dynamic FDG PET imaging [1] [2]. Using this method we tested the hypothesis in mice heart in vivo, that early metabolic remodeling in the form of increased myocardial FDG uptake precedes structural LV remodeling in conjunction with a decrease in cardiac function, in an acute mouse model of transverse aortic constriction (TAC) induced pressure overload LVH [2] [87].…”

“…The key issue is to identify the temporal and causal relationship between metabolic remodeling and impaired cardiac function and the development of LVH, and to define a window for aggressive therapy to prevent disease progression. PET imaging is an excellent tool to address this issue [2][132] [133].…”

“…This advanced method not only improves quantitation but is also repeatable. Using the developed kinetic model, this dissertation also discussed the noninvasive measurement of the myocardial glucose uptake rate ki in mouse heart subjected to transverse aortic constriction (TAC) surgery induced pressure overload left ventricle hypertrophy (LVH), to test the hypothesis that metabolic changes precede and possibly trigger cardiac dysfunction in the pressure overloaded heart [2].…”