Effect of Patent Foramen Ovale Closure After Stroke on Circulatory Biomarkers

Abstract

ObjectiveTo determine the influence of patent foramen ovale (PFO) closure on circulatory biomarkers.MethodsConsecutive patients with PFO-related stroke were prospectively enrolled and followed with serial sampling of cardiac atrial and venous blood pre- and post-PFO closure over time. Candidate biomarkers were identified by mass spectrometry in a discovery cohort first, and lead candidates were validated in an independent cohort.ResultsPatients with PFO-related stroke (n = 254) were recruited and followed up to 4 years (median 2.01; interquartile range 0.77–2.54). Metabolite profiling in the discovery cohort (n = 12) identified homocysteine as the most significantly decreased factor in intracardiac plasma after PFO closure (false discovery rate 0.001). This was confirmed in a validation cohort (n = 181), where intracardiac total homocysteine (tHcy) was immediately reduced in patients with complete closure, but not in those with residual shunting, suggesting association of PFO shunting with tHcy elevation (β 0.115; 95% confidence interval [CI] 0.047–0.183; p = 0.001). tHcy reduction was more dramatic in left atrium than right (p < 0.001), suggesting clearance through pulmonary circulation. Long-term effect of PFO closure was also monitored and compared to medical treatment alone (n = 61). Complete PFO closure resulted in long-term tHcy reduction in peripheral blood, whereas medical therapy alone showed no effect (β −0.208; 95% CI −0.375∼-0.058; p = 0.007). Residual shunting was again independently associated with persistently elevated tHcy (β 0.184; 95% CI 0.051–0.316; p = 0.007).ConclusionsPFO shunting may contribute to circulatory tHcy elevation, which is renormalized by PFO closure. PFO is not just a door for clots, but may itself enhance clot formation and injure neurovasculature by clot-independent mechanisms. Biomarkers such as tHcy can potentially serve as cost-effective measures of residual shunting and neurovascular risk for PFO stroke.