Examining the relationship between exercise tolerance and isoproterenol-based cardiac reserve in murine models of heart failure

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 heart failure; however, treadmill performance and at-rest cardiac indices determined by magnetic resonance imaging (MRI) rarely correlate. The current 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 (VO2 max) vs. sham at 15 weeks post-surgery (WPS). MI and sham mice had similar VO2 max 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 EF under ISO stress was reduced in HF mice at 4WPS (10.1±3.9 Δ% and 8.9±3.5 Δ% in MI and TAC respectively, compared to 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 indices under ISO stress. In conclusion, ISO stress was unable to reflect consistent differences in ETT between HF and healthy mice, suggesting cardiac-specific indices are not the sole factors in defining exercise intolerance in mouse HF models.