title: Examining the relationship between exercise tolerance and isoproterenol-based cardiac reserve in murine models of heart failure.
abstract: The loss of cardiac reserve is, in part, responsible for exercise intolerance in late-stage heart failure (HF). Exercise tolerance testing (ETT) has been performed in mouse models of HF; however, treadmill performance and at-rest cardiac indexes determined by magnetic resonance imaging (MRI) rarely correlate. The present study adopted a stress-MRI technique for comparison with ETT in HF models, using isoproterenol (ISO) to evoke cardiac reserve responses. Male C57BL/6J mice were randomly subjected to myocardial infarction (MI), transverse aortic constriction (TAC), or sham surgery under general anesthesia. Mice underwent serial ETT on a graded treadmill with follow-up ISO stress-MRI. TAC mice showed consistent exercise intolerance, with a 16.2% reduction in peak oxygen consumption vs. sham at 15-wk postsurgery (WPS). MI and sham mice had similar peak oxygen consumption from 7 WPS onward. Time to a respiratory exchange ratio of 1.0 correlated with ETT distance (r = 0.64; P < 0.001). The change in ejection fraction under ISO stress was reduced in HF mice at 4 WPS [10.1 ± 3.9% change (Δ) and 8.9 ± 3.5%Δ in MI and TAC, respectively, compared with 32.0 ± 3.5%Δ in sham; P < 0.001]. However, cardiac reserve differences between surgery groups were not observed at 16 WPS in terms of ejection fraction or cardiac output. In addition, ETT did not correlate with cardiac indexes under ISO stress. In conclusion, ISO stress was unable to reflect consistent differences in ETT between HF and healthy mice, suggesting cardiac-specific indexes are not the sole factors in defining exercise intolerance in mouse HF models.
authors: Heart Failure Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapy Area Unit, GlaxoSmithKline, King of Prussia, Pennsylvania 19406, USA.
authors: Daniel A
authors: DA
authors: Richards
authors: Weike
authors: W
authors: Bao
authors: Mary V
authors: MV
authors: Rambo
authors: Mark
authors: M
authors: Burgert
authors: Beat M
authors: BM
authors: Jucker
authors: Stephen C
authors: SC
authors: Lenhard
mesh_terms: D000318:Adrenergic beta-Agonists; D000818:Animals; D002316:Cardiotonic Agents; D004195:Disease Models, Animal; D005080:Exercise Test; D017079:Exercise Tolerance / Q000502:physiology; D006333:Heart Failure / Q000209:etiology / Q000503:physiopathology*; D006801:Humans; D007545:Isoproterenol; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000150:complications; D010101:Oxygen Consumption; D005082:Physical Exertion / Q000502:physiology*; D016277:Ventricular Function, Left
chemical_list: D000318:Adrenergic beta-Agonists; D002316:Cardiotonic Agents; D007545:Isoproterenol
keywords: magnetic resonance imaging; myocardial infarction; transverse aortic constriction; treadmill