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 uptake of the myocardial glucose analog 18F-FDG precedes and triggers the onset of severe contractile dysfunction in pressure-overload left ventricular hypertrophy in vivo. To test this hypothesis, we used a mouse model of transverse aortic constriction (TAC) together with PET and assessed serial changes in cardiac metabolism and function over 7 d. Methods: Scans of 16 C57BL/6 male mice were obtained using a small-animal PET device under sevoflurane anesthesia. A 10-min transmission scan was followed by a 60-min dynamic 18F-FDG PET scan with cardiac and respiratory gating. Blood glucose levels were measured before and after the emission scan. TAC and sham surgeries were performed after baseline imaging. Osmotic mini pumps containing either propranolol (5 mg/kg/d) 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 spillover and partial-volume corrections and the metabolic rate constants in a 3-compartment model are simultaneously estimated, was used to determine the net myocardial 18F-FDG influx constant, Ki. The rate of myocardial glucose utilization, rMGU, was also computed. Estimations of the ejection fractions were based on the high-resolution gated PET images. Results: Mice undergoing TAC surgery exhibited an increase in the Ki (580%) and glucose utilization the day after surgery, indicating early adaptive response. On day 7, the ejection fraction 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 the rate of 18F-FDG uptake, diminished mismatch between Ki and rMGU (9%), and rescued cardiac function. Conclusion: Metabolic maladaptation precedes the onset of severe contractile dysfunction. Both are prevented by treatment with propranolol. The early detection of metabolic remodeling may offer a metabolic target for modulation of hypertrophy. COPYRIGHT © 2013 by the Society of Nuclear Medicine and Molecular Imaging, Inc.