Logically, by Fick’s principle,26,36‐38 the ratio of oxygen uptake to ventilation (ie, OUE = o2/ e), should evaluate cardiovascular performance, as it is dependent on three factors: cardiac output, arterial-mixed venous oxygen content difference, and lung ventilation.26,36‐38 The OUEP tended to be higher in healthier individuals.24 For reasons that may not be intuitively obvious, in both normal subjects24 and patients with HF, the OUE was not highest at rest or at maximal exercise, but during moderate exercise (Fig 1). The highest OUE (OUEP) does not occur at rest because cardiac output is lowest; ventilation is less efficient (anatomic dead space volume is a higher proportion of tidal volumes); and arterial-mixed venous oxygen content difference is lowest because the oxygen saturation of mixed venous blood is higher both in normal subjects and patients at rest than during exercise (so that not as much O2 can be extracted from inhaled air at rest). In both normal subjects24 and patients with HF, the OUEP does not occur at heavy, very heavy, or maximal exercise, even though mixed venous oxyhemoglobin saturation is low and the ratio of anatomic dead space to alveolar ventilation is optimal. This is because, with more intense exercise, increasing production of lactate, metabolic CO2, excess CO2, and increasing H+ stimulate ventilation. Because ventilation does not normally limit exercise, this stimulation results in increasing CO2 output but less increasing O2 loading equally, lowering the alveolar and arterial CO2 partial pressure. This, in turn, further reduces ventilatory efficiency as more ventilation is required to remove CO2 to balance the declining bicarbonate levels and reduce acidemia. As exercise intensity increases, ventilatory drive to reduce acidemia decreases co2/ e and o2/ e (equivalent to increasing e/ co2 and e/ o2). The time of decreasing o2/ e at AT (Fig 1) is earlier than that of decreasing co2/ e at the ventilatory compensation point.26 Thus, the OUEP occurs during less than maximal exercise (below AT level) in both normal subjects24 and patients with HF. It assesses the optimal capacity to match the increasing lung perfusion of mixed venous partially deoxygenated blood with the increasing ventilation and to load O2 into the systemic circulation. In normal subjects and patients with HF without significant ventilatory limitation or primary lung disease, the OUEP appears to reflect overall cardiovascular function of loading and transporting O2 well. Initially, the OUEP was found to be dependent on age, sex, body size, and fitness in over 474 healthy subjects; reference equations from 417 normal subjects were presented.24 Now, it is evident that the OUEP also indicates disease severity in over 500 patients with HF (Fig 1, Table 3). In these patients, the % predicted OUEP, based on age, sex, and height, turns out to be the strongest single predictor of early survival (Figs 3A, 4). While the e- co2 relationship better reflects ventilatory efficiency,25,26 the OUEP appears to better reflect the efficiency of oxygen uptake, which depends on systemic and lung perfusion, just before ventilation is stimulated by exercise-induced acidemia.