Background - Left ventricular assist devices (LVAD) reverse ventricular, myocardial, and systemic abnormalities characteristic of severe heart failure (reverse remodeling). The relative contributions of hemodynamic unloading and normalized biochemical milieu to reverse remodeling are unknown. Methods and Results - Structural and functional characteristics were measured from 53 hearts of patients undergoing transplantation without LVAD support (medical support) and 33 hearts from patients receiving a median of 46 days of LVAD support (range, 8 to 360 days). Compared with medical support alone, patients receiving LVAD support for ≥30 days had higher central venous pressures (11±6 versus 8±5 mm Hg, P=0.04), lower pulmonary artery diastolic pressures (14±9 versus 21±9 mm Hg, P=0.01), and higher cardiac outputs (5.1±1.6 versus 3.7±1.0 L/rain, P<0.001). In LVAD versus transplantation hearts, V30 (ex vivo volume yielding ventricular pressure of 30 mm Hg) was decreased in the left ventricle (LV) (179±75 versus 261±118 mL, P=0.005) but not in the right ventricle (RV) (140±59 versus 148±52 mL, P=NS). LV myocyte diameter decreased more significantly after LVAD support (17%, P-0.05) than in the RV (11%, P=NS). Compared with transplantation, LVAD support increased normalized SERCA2a content in the LV (0.51±0.26 versus 1.04±0.34, P<0.001) but not in the RV (0.48±34 versus 0.67±0.55, P=NS). Finally, LVAD support improved force-frequency relations of isolated superfused LV trabeculae (P=0.01) but not RV trabeculae. Conclusions - Reduction of hemodynamic load is a primary factor underlying several important features of reverse remodeling. These findings do not preclude a possible primary role of neurohormonal factors underlying other facets of reverse remodeling during LVAD support.