Mucus plugs in COPD and cardiovascular mortality: An emerging risk pathway and the therapeutic potential of mucolytic strategies

Airway mucus plugging is an underrecognized feature of COPD that is increasingly associated with adverse outcomes, including higher mortality rates. Computed tomography studies demonstrate that mucus plugs are prevalent, variable, and frequently persistent or dynamic over time. The presence of mucus plugs is independently linked to a worse prognosis, even after adjusting for cardiovascular and respiratory risk factors. Patients with mild COPD appear to be at particularly high risk, suggesting that mucus plugging may represent an early and potentially modifiable disease trait. Mucus plugging contributes to COPD progression through several mechanisms, including airflow obstruction, ventilation/perfusion mismatch, hypoxemia, airway inflammation, and increased susceptibility to infectious exacerbations. These exacerbations are strongly associated with acute cardiovascular events caused by systemic inflammation, endothelial dysfunction, and vascular stress. Additionally, chronic hypoxia and inflammatory signaling related to mucus dysfunction may independently increase cardiovascular risk. Within the "treatable traits" framework, mucus dysfunction is an important therapeutic target. Mucolytic and mucoactive therapies aim to improve mucus properties and clearance, which could reduce exacerbations and their systemic consequences. Some meta-analytic evidence suggests that, among thiol-based mucolytics, erdosteine is the most effective at reducing exacerbation frequency and duration. It also demonstrates antioxidant and anti-inflammatory effects that may influence systemic disease pathways. However, its comparative advantages over other agents remain uncertain. This narrative review summarizes the current evidence regarding the epidemiology, pathophysiology, and clinical implications of mucus plugging in COPD, with a focus on the proposed mucus plug-exacerbation-cardiovascular event axis and the potential role of mucus-directed therapies.