Although several excellent indices of myocardial contractility exist, they require accurate measurement of pressure using left ventricular (LV) catheterization. Here we validate a novel non-invasive contractility index that is only dependent on lumen and wall volume of LV chamber in patients with normal and compromised LV ejection fraction (LVEF). An analysis of myocardial chamber as a thick-walled sphere results in an LV contractility index expressed as the maximum rate of change of pressure-normalized stress (d*/dt_max where *=/P and and P are circumferential stress and pressure, respectively). To validate this parameter, d*/dt_max was determined from contrast cine ventriculography-assessed LV cavity and myocardial volumes, and compared with LVEF, dP/dt_max, maximum active elastance, Ea,max and single-beat end-systolic elastance, Ees(SB), in 30 patients undergoing clinically-indicated LV catheterization. Patients with different tertiles of LVEF exhibit statistically significant differences in d*/dt_max values. d*/dt_max correlated significantly with dP/dt_max (d*/dtmax = 0.0075 dP/dt_max - 4.70, r =0.88, p<0.01), Ea,max (d*/dtmax = 1.20Ea,max + 1.40, r=0.89, p<0.01), and Ees(SB) (ds*/dt_max = 1.60 Ees(SB) + 1.20, r =0.88, p<0.01). In 30 additional patients, we determined the sensitivity of the parameter to changes in preload (intravenous saline infusion), afterload (sublingual glyceryl trinitrate) and increased contractility (intravenous dobutamine; 10 patients in each group). We confirmed that the index is load-independent but is sensitive to changes in contractility. In conclusion, ds*/dt_max is equivalent to dP/dt_max, Ea,max and Ees(SB) as an index of myocardial contractility, and appears to be load independent. Unlike other measures of contractility, d*/dt_max can be assessed with non-invasive cardiac imaging which should garner more routine clinical applicability.