Patent foramen ovale as a high-risk marker in coronary artery disease patients: response to Dr Ashish H. Shah

We sincerely thank Dr Shah for his interest in our work and for his insightful and thought-provoking comments, which affirm that our topic is a priority for the research community. In this large, retrospective cohort of coronary artery disease (CAD) patients, we found that patent foramen ovale (PFO) was associated with long-term major adverse cardiovascular events (MACE).1 We acknowledge the inherent limitations of a retrospective design and will address them in future studies. Dr Shah’s first concern is that the retrospective design inherently introduces selection bias, potentially enriching the PFO-positive cohort with high-risk confounders, specifically smoking, premature familial CAD, and more severe luminal stenosis, that could independently drive the observed outcome differences. In this study, we adjusted for clinical and coronary computed tomography angiography (CCTA) quantitative plaque parameters through multivariable analysis and performed propensity-score matching between patients with and without PFO based on clinical cardiovascular risk factors and CCTA-derived plaque burden; in the matched cohort, patients with PFO still exhibited a higher cumulative incidence of MACE. The present data alone are insufficient to establish a direct causal link between PFO and severe cardiovascular events in patients with CAD. Nevertheless, our findings raise a novel hypothesis, advance the current understanding of both CAD and PFO, and underscore the need for further mechanistic investigation by the research community. A prospective registry trial using photon-counting computed tomography (PCCT); its longitudinal design will allow us to formally validate the present findings.