Exercise capacity and cardiac hemodynamic response in female $ApoE/LDLR^{-/-}$ mice : a paradox of preserved $VO_{2max}$ and exercise capacity despite coronary atherosclerosis

We assessed exercise performance, coronary blood flow and cardiac reserve of female $ApoE/LDLR^{-/-}$ mice with advanced atherosclerosis compared with age-matched, wild-type C57BL6/J mice. Exercise capacity was assessed as whole body maximal oxygen consumption ($V'O_{2max}$), maximum running velocity ($v_{max}$) and maximum distance ($DIST_{max}$) during treadmill exercise. Cardiac systolic and diastolic function in basal conditions and in response to dobutamine (mimicking exercise-induced cardiac stress) were assessed by Magnetic Resonance Imaging (MRI) in vivo. Function of coronary circulation was assessed in isolated perfused hearts. In female $ApoE/LDLR^{-/-}$ mice $V'O_{2max}$, $v_{max}$ and $DIST_{max}$ were not impaired as compared with C57BL6/J mice. Cardiac function at rest and systolic and diastolic cardiac reserve were also preserved in female $ApoE/LDLR^{-/-}$ mice as evidenced by preserved fractional area change and similar fall in systolic and end diastolic area after dobutamine. Moreover, endothelium-dependent responses of coronary circulation induced by bradykinin (Bk) and acetylcholine (ACh) were preserved, while endothelium-independent responses induced by NO-donors were augmented in female $ApoE/LDLR^{-/-}$ mice. Basal COX-2-dependent production of 6-keto-$PGF_{1\alpha}$ was increased. Concluding, we suggest that robust compensatory mechanisms in coronary circulation involving $PGI_{2}$- and NO-pathways may efficiently counterbalance coronary atherosclerosis-induced impairment in $V'O_{2max}$ and exercise capacity.