The use of veno-arterial (VA) extracorporeal membrane oxygenation (ECMO) to support patients with acute heart failure has been associated with ventricular distension and pulmonary edema, the mechanism of which is not fully understood. This study examined the impact of VA ECMO on left ventricular (LV) Starling curves to elaborate a framework for anticipating and treating LV distension. A previously developed and validated model of the cardiovascular system was used to generate pressure–volume (PV) loops and Starling curves while holding mean arterial pressure (mABP) constant at a range of values either by adjusting systemic resistance or by adding VA ECMO support. It was found that under all conditions of similar mAPB, the Starling curve was unchanged; therefore, the degree of LV distension is obligated by the mAPB (irrespective of whether controlled pharmacologically with or without ECMO support and independent of heart rate), LV contractility, and target stroke volume. The Starling relationship provides a conceptual framework for understanding the risk and treatment of LV distension during VA ECMO support.