OBJECTIVES: The purpose of this study was to provide insight into the potential for left atrium (LA) to aortic mechanical circulatory support as a treatment for patients with heart failure with preserved ejection fraction (HFpEF). BACKGROUND: Although HFpEF arises from different etiologies, 1 hallmark of all forms of this syndrome is a small or minimally-dilated left ventricle (LV). Consequently, the use of traditional mechanical circulatory support in end-stage patients has been difficult. In contrast, HFpEF is also characterized by a large LA. METHODS: Hemodynamic characteristics of 4 distinct HFpEF phenotypes were characterized from the published data: 1) hypertrophic cardiomyopathies; 2) infiltrative diseases; 3) nonhypertrophic HFpEF; and 4) HFpEF with common cardiovascular comorbidities (e.g., hypertension). Employing a previously-described cardiovascular simulation, the effects of a low-flow, micropump-based LA decompression device were modeled. The effect of sourcing blood from the LV versus the LA was compared. RESULTS: For all HFpEF phenotypes, mechanical circulatory support significantly increased cardiac output, provided a mild increase in blood pressure, and markedly reduced pulmonary and LA pressures. LV sourcing of blood reduced LV end-systolic volume into a range likely to induce suction. With LA sourcing, however, LV end-systolic volume increased compared with baseline. Due to pre-existing LA enlargement, LA volumes remained sufficiently elevated, thus minimizing the risk of suction. CONCLUSIONS: This theoretical analysis suggests that a strategy involving pumping blood from the LA to the arterial system may provide a viable option for end-stage HFpEF. Special considerations apply to each of the 4 types of HFpEF phenotypes described. Finally, an HFpEF-specific clinical profile scoring system (such as that of INTERMACS [Interagency Registry for Mechanically Assisted Circulatory Support]) would aid in the selection of patients with the appropriate risk-benefit ratio for implantation of an active pump.