Patent Foramen Ovale: Innocent or Guilty?: Evidence From a Prospective Population-Based Study Irene Meissner, Bijoy K. Khandheria, John A. Heit, George W. Petty, Sheldon G. Sheps, Gary L. Schwartz, Jack P. Whisnant, David O. Wiebers, Jody L. Covalt, Tanya M. Petterson, Teresa J. H. Christianson, Yoram Agmon Reported stroke risk in patients with patent foramen ovale ranges widely from <1% to as high as 17.5%, reflecting methodologic weaknesses, including retrospective design, invalid controls, unblinded transesophageal echocardiography examinations, and data that are unadjusted for age or comorbidity. This to-date largest prospective study population-based transesophageal echocardiography study demonstrated that, after adjustment for age/comorbidity, patent foramen ovale was not a significant independent predictor of stroke (hazard ratio 1.46, 95% confidence interval 0.74 to 2.88, p = 0.28). The risk of a cerebrovascular event with atrial septal aneurysm was nearly four times that without atrial septal aneurysm; however, a larger study is required to test this putative association. We sought to determine the association between patent foramen ovale (PFO), atrial septal aneurysm (ASA), and stroke prospectively in a unselected population sample. The disputed relationship between PFO and stroke reflects methodologic weaknesses in studies using invalid controls, unblinded transesophageal echocardiography examinations, and data that are unadjusted for age or comorbidity. The use of transesophageal echocardiography to identify PFO was performed by a single echocardiographer using standardized definitions in 585 randomly sampled, Olmsted County (Minnesota) subjects age 45 years or older participating in the Stroke Prevention: Assessment of Risk in a Community (SPARC) study. A PFO was identified in 140 (24.3%) subjects and ASA in 11 (1.9%) subjects. Of the 140 subjects with PFO, 6 (4.3%) had an ASA; of the 437 subjects without PFO, 5 had an ASA (1.1%, two-sided Fisher exact test, p = 0.028). During a median follow-up of 5.1 years, cerebrovascular events (cerebrovascular disease-related death, ischemic stroke, transient ischemic attack) occurred in 41 subjects. After adjustment for age and comorbidity, PFO was not a significant independent predictor of stroke (hazard ratio 1.46, 95% confidence interval 0.74 to 2.88, p = 0.28). The risk of a cerebrovascular event among subjects with ASA was nearly four times higher than that in those without ASA (hazard ratio 3.72, 95% confidence interval 0.88 to 15.71, p = 0.074). These prospective population-based data suggest that, after correction for age and comorbidity, PFO is not an independent risk factor for future cerebrovascular events in the general population. A larger study is required to test the putative stroke risk associated with ASA.