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In chronic cardiopulmonary disease, functional impairment develops in all oxygen transport organs, regardless of the specific cause of the disease. Some abnormalities, such as pulmonary edema in heart failure or right ventricular failure in destructive lung disease, are direct consequences of the primary pathological process. Others, such as skeletal muscle dysfunction that cannot be fully ascribed to edema, electrolyte imbalance, or exogenous medication or fully reversed by physical training or supplemental oxygen, seem paradoxical and resemble changes during acclimatization to high altitude. To understand these secondary responses, the lung-heart muscle axis must be considered as an integrated unit. Then, it becomes apparent that oxygen transport is regulated like any other metabolic pathway, whether organized at a systemic, organ, cellular, or subcellular level, and it follows established principles of metabolic control. Of particular importance is the concept of coordinated adaptation, where a single disturbance in a multistep pathway triggers adaptation in other steps to seek new levels of functional equilibrium within the constraints imposed by the primary disorder. This article discusses (1) fundamental principles of metabolic control, (2) adaptive mechanisms in oxygen transport, (3) coordinated adaptation as a unifying concept to explain diverse secondary responses in disturbed oxygen transport and how seemingly paradoxical responses may, in fact, be beneficial if the underlying physiology is understood, and (4) clinical application of this concept to therapy.In a biological system, load is the flux through the system (Figure 1A), ie, rate of substrate conversion to the product or translocation from one point to another. Capacity is the maximum achievable load, and reserve is the difference between load and capacity. Across a wide range of systems and species, the capacity-to-load ratio is remarkably constant, suggesting a fundamental need for maintaining physiological reserves. When capacity is reduced but still adequate for the expected loads, …

Coordinated Adaptation of Oxygen Transport in Cardiopulmonary Disease