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.

A novel method for high precision aortic constriction that allows for generation of specific cardiac phenotypes in mice

“…In comparable suture-based TAC studies, the average 2-week survival rate is 78% after constriction of the ascending aorta [38][39][40] and 73% after constriction of the transverse aorta. [15][16][17][18][19]21 The majority of these early deaths are reportedly due to acute HF, suggesting excessive constriction. We believe that standardization of the constriction and avoidance of total occlusion during the procedure 41 were responsible for the negligible mortality observed with ORAB.…”

“…substantially, i.e. <25%, [13][14][15][16] 25-50%, [17][18][19] and 50-75%. 7,20,21 Such variations obviously complicate and confound the interpretation of mechanistic data.…”

Activation of the Amino Acid Response Pathway Blunts the Effects of Cardiac Stress

“…Transverse aortic constriction (TAC) was performed as previously reported . Briefly, mice were anesthetized with pentobarbital (Nembutal) and ventilated.…”

Using Exercise to Measure and Modify Cardiac Function

“…More commonly, an indirect inference is made by documenting a reduction in exercise capacity and cardiac abnormalities at rest, frequently by echocardiography. The potential pitfalls of using this approach are illustrated by a recent paper using two models of a cardiac-specific intervention, myocardial infarction and pressure overload (thoracic aortic constriction) (Richards et al, 2013). .…”