The fundamental importance of cardiac shortening and lengthening velocity (i.e. strain rate; SR) has been demonstrated in vitro. Currently, the interdependence between in vivo SR and HR is poorly understood because studies have typically assessed region-averaged ‘longitudinal’ strain rate, which is likely to underestimate the apical contribution, and have used non-physiological interventions that may also have been influenced by multicollinearity caused by concomitant reductions in arterial resistance. Resistance exercise acutely raises HR, blood pressure and arterial resistance and transiently disassociates these cardiovascular factors following exercise. Therefore, we measured SR, HR, blood pressure and arterial resistance in nine healthy men (aged 20 ± 1 years) immediately before, during and after double-leg-press exercise at 30 and 60% of maximal strength. Resistance exercise caused a disproportionate SR response at the left ventricular base and apex (interaction effect, P < 0.05). Consequently, associations between HR and regional peak SR were inconsistent and mostly very weak (r2 = 0.0004–0.24). Likewise, the areas under the curve for systolic and diastolic SR and their relationship with systolic and diastolic duration were variable and weak. Importantly, region-averaged ‘longitudinal’ SR was identical to basal SR, thus, markedly underestimating the apical contribution. In conclusion, in vivo HR and SR are not strictly coupled in healthy humans, which is explained by the region-specific responses of SR that are not captured by ‘longitudinal SR’. This novel observation emphasizes the independent role of in vivo SR in overall cardiac function during stress and may cause a ‘revival’ of SR as a marker of regional left ventricular (dys)function.