Sphericalization of left ventricular (LV) chamber shape in patients with mitral regurgitation (MR) contributes to increased LV wall stress and energy consumption. Based on previous observations, we hypothesized the existence of regional differences in the force-frequency relation (FFR) within the left ventricle (LV) that may contribute to its shape. Accordingly, in the present study we assessed regional variation in the FFR in patients undergoing surgery for chronic, non-ischemic MR with Class II-III heart failure symptoms and related our findings to in vivo LV shape. FFRs (steady-state isometric twitches, 0.2 to 3.4 Hz, 37° C) were evaluated in MR myocardium from the LV subepicardial freewall (MR-FW) and papillary muscle (MR-PM) and from the subepicardial freewall in coronary artery bypass graft patients with normal LV contraction patterns [non-failing (NF)]. Ascending slope, optimal stimulation frequency, and maximal twitch tension of the FFR were depressed in MR-FW and MR-PM compared with NF (p < 0.05). FFR depression was greater in MR-PM than in MR-FW. Between 107 bpm and 134 bpm twitch tension became weaker in MR-PM while it increased in MR-FW. Elevation of intracellular cyclic-AMP with forskolin eliminated FFR depression in MR-FW but not in MR-PM. MR-PM also had 35% lower myosin heavy chain content and slowed twitch kinetics. In MR patients echocardiographic end-diastolic LV shape [end-diastolic eccentricity index (EDEI) = long axis /short axis] correlated with the ratio of ascending FFR slopes (R_FW/R_PM), such that EDEI increased 10% per 15% increase in slope ratio (r = 0.88, p = 0.01). These regional differences in the frequency dependence of contractility between freewall and papillary myocardium may contribute to changes in LV shape in MR as well as during exercise.