Background: Veno-arterial extra-corporeal membrane oxygenation (VA-ECMO) may cause adverse effects including increased left ventricular (LV) filling pressure, LV distension and pulmonary oedema. We aimed to quantify the effects of ECMO flow, LV contractility, aortic pressure (AoP) and ECMO configuration on left atrial pressure (LAP) during VA-ECMO for cardiogenic shock in a mock circulatory loop (MCL). Methods: An MCL simulated a normal state, LV failure, right ventricular failure and biventricular failure. The ECMO return cannula was placed in the femoral artery (retrograde flow) or ascending aorta (antegrade flow). ECMO flow was incrementally increased from 0 to 5L/min. LAP, mean AoP, ECMO flow and total cardiac output were measured at steady state. Results: During VA-ECMO, LAP increased linearly with AoP, with the slope greater in the presence of LV impairment compared to preserved LV function. When AoP was held constant, as is the goal of therapy in clinical management, ECMO flow had no effect on LAP. In multivariable linear regression, AoP and LV contractility (p<0.001 for each) correlated independently with LAP, but ECMO flow did not. ECMO return flow direction had no effect on LAP. Conclusion:AoP and LV contractility, but not circuit flow or direction, independently determine LAP under VA-ECMO support. By controlling each of these inputs, vasodilator and inotrope management may combine synergistically to prevent VA-ECMO-related complications.