Heart failure with preserved ejection fraction (HFpEF) is a syndrome that accounts for about one-half of all chronic heart failure patients. To assess changes in regional biventricular circumferential, longitudinal, and radial strains associated with this syndrome, we developed a semi-automated strain quantification pipeline based on the hyperelastic warping method. The strain quantification method was applied to the cardiac magnetic resonance images of 10 HFpEF patients and 10 healthy individuals serving as control. Consistent with previous clinical findings, we found that the peak systolic LV circumferential strain Ecc and longitudinal strain Ell were significantly depressed compared to the control (Ecc: -9.37 ± 3.23% vs. -15.5 ± 1.90%; Ell: -11.3 ± 1.76 vs. -15.6 ± 2.06%). This result, together with similar findings from other clinical studies, suggests that systolic function and myocardial contractility may be also impaired in HFpEF. However, it is also known that increased afterload resistance and pressure can also decrease LV strains. It is not possible, based on these strain measurements only, to determine if the decreased strain in HFpEF is simply due to the increased afterload, or whether it is truly indicative of reduced myocardial contractility. To address this issue, we used a validated computational modeling framework to isolate the effects of both hypothesized and established factors deemed to affect longitudinal strain in HFpEF, namely, changes in 1) active tension developed by the tissue (i.e., myocardial contractility), 2) ventricular afterload as indexed by arterial resistance, 3) LV geometry and passive stiffness and 4) combinations of these factors. We showed that indeed, after accounting for changes in geometry, muscle mass and afterload, the depressed strains found in HFpEF patients reflects a reduction in myocardial contractility. This finding may have important clinical implication in the development of treatment strategies for HFpEF.