Using Isoprenaline To Explore The Relationship Between Exercise And Drug-Induced Cardiac Reserve In Heart Failure Mice

Daniel Richards1,2, Stephen Lenhard1, Weike Bao1, Mary Rambo1. 1GlaxoSmithKline, King of Prussia, PA, USA, 2University of Bristol, Bristol, Avon, UK.

Introduction: Exercise intolerance is the most common heart failure (HF) symptom, leading to a detrimental effect on patient quality of life. To better understand the principles behind exercise intolerance in the research setting, cardiac magnetic resonance imaging (MRI) is used to support mouse treadmill tests. However, treadmill performance and at-rest cardiac indices rarely correlate.

Cardiac reserve is the ability of the heart to elevate from basal function to meet heightened demands of the body, and hence is regarded as a better reflection of exercise tolerance. Since isoprenaline activates β1-adrenoceptors in the heart and mimics the effects of exercise, it can be used in conjunction with MRI to uncover cardiac reserve. Using myocardial infarction (MI) and transverse aortic constriction (TAC) surgical models of mouse HF, we sought to investigate the currently unknown relationship between exercise and isoprenaline-induced cardiac reserve. It was hypothesized that treadmill performance would be reduced in HF mouse models compared to controls, and correspond to a reduced MRI-derived cardiac reserve.

Methods: Under Nembutal anaesthesia, male C57BL/6J mice were randomly given either MI (n = 34), TAC (n = 16) or sham control (n = 10) surgery. Mice were followed for 4 months with monthly exercise tolerance tests (ETTs) consisting of a run to exhaustion on a graded treadmill. An MRI with integrated cardiac reserve test (isoprenaline 1mg/kg BW i.p.) under anaesthesia (2% isoflurane), was conducted one week after each ETT. MI and TAC were directly compared to sham mice using a student’s t-test for total running distance, peak oxygen consumption (VO2max), time to RER = 1 and the reserves of cardiac indices, measured as percentage increase from baseline.

Results: TAC mice show early exercise intolerance (394.0±60.0m vs. sham 630.8±46.8m; P<0.01) and a reduced VO2max, both of which are sustained for the study duration. MI mice recover to sham-like exercise tolerances and have similar VO2max values from 7 weeks post-surgery (115.6±3.8 and 120.6±3.1 ml/kg/min for MI and sham respectively; P = 0.83). Time to RER = 1 was found to replicate ETT distance for all groups (Pearson’s r2 = 0.416; P<0.0001). MI and TAC mice frequently show reduced baseline ejection fraction (31.3±4.7% at 4 weeks post-surgery for MI vs. sham 61.8±3.8%; P<0.0001) and other cardiac indices, though most differences are lost during the isoprenaline stress test. The ETT does not correlate with any cardiac index under isoprenaline stress.

Discussion: The TAC HF model is best suited for ETT assessment due to permanent intolerance. Isoprenaline is unable to show consistent differences between HF and healthy mice, indicating that cardiac-specific indices are not sole components in defining exercise intolerance. Isoprenaline should therefore not be assumed to accurately replicate the effects of exercise.