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1 Cardiovascular Medicine, Stanford University Medical Center, Stanford, California, United States
2 Cardiothoracic Surgery, Stanford University Medical Center, Stanford, California, United States
3 Radiology, Stanford University Medical Center, Stanford, California, United States
4 Cardiothoracic Surgery, Stanford University Medical Center, 94305, California, United States
* To whom correspondence should be addressed. E-mail: pyue{at}cvmed.stanford.edu.
Background: The db/db mouse is a well-established model of diabetes mellitus. Previous reports have documented contractile dysfunction (i.e. cardiomyopathy) in these animals, though the extant literature provides limited insights into cardiac structure and function as they change over time. To better elucidate the natural history of cardiomyopathy in db/db mice, we performed cardiac magnetic resonance (CMR) scans on these animals. Methods: CMR imaging was accomplished using a 4.7 T magnet on female db/db mice and control db/+ littermates at 5, 9, 13, 17, and 22 weeks of age. Gated gradient echo sequences were used to obtain cineographic short axis slices from apex to base. From these images left ventricular mass (LVM), wall thickness, end-diastolic volume (LVEDV), and ejection fraction (LVEF) were determined. Additionally, cardiac [18F]-fluorodeoxyglucose positron emission tomography ([18F]-FDG-PET), pressure-volume loops, and real-time quantitative polymerase chain reaction (RT-PCR) on db/db myocardium were performed. Results: Relative to control, db/db mice developed significant increases in LVM and wall thickness as early as 9 weeks of age. LVEDV diverged slightly later at 13 weeks. Interestingly, compared to their baseline level, LVEF in the db/db group did not decrease significantly until 22 weeks. In support of these findings, [18F]-FDG-PET scanning showed a 40% decrease in glucose uptake in db/db mice. Additionally, contractile dysfunction was observed in 15-week db/db mice undergoing pressure-volume loops. Finally, RT-PCR revealed an age-dependent recapitulation of the fetal gene program, consistent with a myopathic process. Conclusions: As assessed by CMR, db/db mice develop characteristic structural and functional changes consistent with cardiomyopathy.
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