Pathophysiological mechanisms of exertional dyspnea in people with cardiopulmonary disease: Recent advances

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. • Exertional dyspnea reflects high respiratory demand relative to low-capacity • Excessive breathing is secondary to hyperventilation and/or high wasted ventilation • Excessive breathing is the key driver of dyspnea in heart failure and pulmonary vascular disease • Constrained breathing is associated with mechanical restraints to tidal volume expansion • Constrained breathing is the primary mechanism of exertional dyspnea in obstructive and restrictive lung diseases

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