Temporal Dynamics of Cardiovascular Risk in Patients with Chronic Obstructive Pulmonary Disease During Stable Disease and Exacerbations: Review of the Mechanisms and Implications

Sami O Simons,1,2 Amy B Heptinstall,3 Zoe Marjenberg,3 Jonathan Marshall,4 Hana Mullerova,4 Paola Rogliani,5 Clementine Nordon,4 Nathaniel M Hawkins6 1Department of Respiratory Medicine, NUTRIM Institute for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands; 2Department of Respiratory Medicine, Maastricht University Medical Centre, Maastricht, The Netherlands; 3Maverex Ltd, Newcastle Upon Tyne, UK; 4BioPharmaceuticals Medical, Respiratory and Immunology, AstraZeneca, Cambridge, UK; 5Department of Experimental Medicine, Unit of Respiratory Medicine, University of Rome ‘Tor Vergata’, Rome, Italy; 6Cardiology, University of British Columbia, Vancouver, CanadaCorrespondence: Clementine Nordon, AstraZeneca, Academy House, 136 Hills Road, Cambridge, CB2 8PA, UK, Email [email protected]: Exacerbations of chronic obstructive pulmonary disease (COPD) are risk factors for severe cardiovascular (CV) events, with the risk remaining significantly elevated long after the symptomatic phase of the exacerbation. The pathophysiology underpinning the relationship between acute events of both COPD and CV diseases has been understudied. Our objectives were to review the mechanisms by which COPD exacerbations increase the risk of CV events and understand the temporality of this risk.Methods: A pragmatic and targeted literature review was conducted with a focus on identifying recent, high-impact papers up to June 2023, guided by insights from subject matter experts including pulmonologists and cardiologists.Results: A substantial number of inter-related mechanisms underpin the spiral of anatomical and functional deterioration of lung and heart affecting COPD patients during stable state. In turn, an exacerbation of COPD may trigger a CV event, during and beyond the symptomatic phase, due to ventilation/perfusion mismatch, oxygen supply-demand imbalance, oxidative stress, systemic inflammation, hypercoagulable state, dynamic hyperinflation, pulmonary hypertension, and sympathetic activation. However, no study was identified that explored the mechanisms by which an exacerbation confers a sustained risk of CV event.Conclusion: While our review identified multiple dynamic and interacting pathophysiological mechanisms during and after an exacerbation of COPD that contribute to increasing the risk of a wide range of cardiac events, little is known regarding the precise long-term mechanisms after acute exacerbation to explain the persistent increased CV event risk beyond the symptomatic phase. The temporal changes in static and dynamic substrates need further characterization to better understand the different risk factors and risk periods for a CV event following the onset of an exacerbation. Moreover, guideline-directed cardiopulmonary therapies should be implemented at every opportunity; preventing exacerbations and intensively treating traditional CV risk factors should be a focus in COPD management.Keywords: acute events, cardiovascular disease, cardiovascular events, cardiopulmonary