Patent foramen ovale-associated stroke: Historical evolution, clinical presentations, randomized trials, and closure strategies

Abstract

Patent foramen ovale (PFO) is increasingly recognized as an important contributor to cryptogenic ischemic stroke, particularly in younger patients without traditional vascular risk factors. Although present in about one-quarter of the general population, its higher prevalence among patients with otherwise unexplained stroke has raised questions regarding a causal relationship. The most widely accepted mechanism is paradoxical embolism, in which thrombotic material from the venous circulation bypasses the pulmonary filter through a transient right-to-left interatrial shunt. Over time, specific anatomical and clinical factors such as shunt size, the presence of an atrial septal aneurysm, and the overall vascular risk profile have been shown to help differentiate incidental PFO from clinically significant cases. Randomized clinical trials have demonstrated a reduction in recurrent ischemic stroke with percutaneous PFO closure in carefully selected patients, with benefit driven by appropriate patient selection and high-risk anatomical features. Despite these clinical trials and evidence, several uncertainties remain, including the management of older patients, the role of anticoagulation, and the significance of post-procedural atrial fibrillation, which is more common after closure but is typically transient. There is now increasing emphasis on individualized risk stratification using tools such as the Risk of Paradoxical Embolism (RoPE) score and PFO-Associated Stroke Causal Likelihood (PASCAL) classification. This review summarizes the current understanding of PFO-associated stroke, including pathophysiology, clinical presentation, randomized evidence, treatment strategies, and future directions, including emerging evidence on head-to-head device comparison and bioresorbable closure technology.