James MD; Respiratory Investigation Unit, Division of Respirology, Department of Medicine, Queen’s University, Kingston, ON, Canada.
Phillips DB;Domnik NJ; Neder JA;

Respiratory physiology & neurobiology [Respir Physiol Neurobiol] 2025 Mar 29, pp. 104423.
Date of Electronic Publication: 2025 Mar 29.

Physical activity is a leading trigger of dyspnea in chronic cardiopulmonary diseases. Recently, there has been a renewed interest in uncovering the mechanisms underlying this distressing symptom. We start by articulating a conceptual framework linking cardiorespiratory abnormalities with the central perception of undesirable respiratory sensations during exercise. We specifically emphasize that exertional dyspnea ultimately reflects an imbalance between (high) demand and (low) capacity. As such, the symptom arises in the presence of a heightened inspiratory neural drive – the will to breathe – secondary to a) increased ventilatory output relative to the instantaneous ventilatory capacity (excessive breathing) and/or b) its impeded translation into the act of breathing due to constraints on tidal volume expansion (constrained breathing). In patients with chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, and interstitial lung disease (ILD), constrained breathing assumes a more dominant role as the disease progresses. Excessive breathing due to heightened wasted ventilation in the physiological dead space is particularly important in the initial stages of COPD, while alveolar hyperventilation has a major contributory role in hypoxemic patients with ILD. Hyperventilation is also a leading driver of dyspnea in heart failure (HF) with reduced ejection fraction (EF), while high physiological dead space is the main underlying mechanism in HF with preserved EF. Similarly, wasted ventilation in poorly perfused lung tissue dominates the scene in pulmonary vascular disease. New artificial intelligence-based approaches to expose the contribution of excessive and constrained breathing may enhance the yield of cardiopulmonary exercise testing in investigating exertional dyspnea in these patients.