This is consistent with a negative force–frequency relationship that is known to be present in murine hearts.31 Interestingly, in man, there is a positive relationship in the healthy left ventricle but this remodels in heart failure to a negative one32 and has been suggested to be one of the beneficial effects of HR reduction in heart failure.33 However, when undertaking treadmill exercise the Gαs (flx, flx) HCN4 cre + mice after tamoxifen showed reduced exercise ability compared to littermate controls. Here, HCN4 is linked to heart failure.