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Updated: Nov 5, 2025
Closure of a Patent Foramen Ovale PFO: An Intervention Sequence
Published on: December 23, 2022
Effect of Patent Foramen Ovale Closure After Stroke on Circulatory Biomarkers
Wenjun Deng1, David McMullin1, Ignacio Inglessis-Azuaje1
1From the Clinical Proteomics Research Center (W.D., D.M., F.S.B., E.H.L., M.M.N.), Cardio-Neurology Division (W.D., I.I.-A., J.J.L., I.F.P., F.S.B., E.H.L., M.M.N.), and Neuroprotection Research Laboratory (E.H.L., M.M.N.), Massachusetts General Hospital, Harvard Medical School, Boston.
Insights
Patent foramen ovale (PFO) closure significantly reduces elevated homocysteine levels in patients with PFO-related stroke. This suggests PFO contributes to stroke risk through mechanisms beyond clot formation, with homocysteine as a potential biomarker.
Area of Science:
- Cardiovascular Medicine
- Neurology
- Biomarker Discovery
Background:
- Patent foramen ovale (PFO) is a common cardiac anomaly associated with cryptogenic stroke.
- The precise mechanisms by which PFO contributes to stroke, beyond paradoxical embolism, remain incompletely understood.
- Circulatory biomarkers may offer insights into PFO-associated pathophysiology and neurovascular risk.
Purpose of the Study:
- To investigate the influence of patent foramen ovale (PFO) closure on specific circulatory biomarkers.
- To identify and validate biomarkers that reflect the hemodynamic and metabolic consequences of PFO shunting.
- To assess the potential of biomarkers for monitoring PFO closure efficacy and neurovascular risk.
Main Methods:
- Prospective enrollment of 254 patients with PFO-related stroke.
- Serial blood sampling (atrial and venous) pre- and post-PFO closure.
- Mass spectrometry for biomarker discovery in a subset (n=12), followed by validation in a larger cohort (n=181).
Main Results:
- Intracardiac homocysteine (tHcy) was significantly reduced after successful PFO closure, with no reduction in cases of residual shunting.
- tHcy reduction was more pronounced in the left atrium, suggesting pulmonary circulation clearance.
- Long-term follow-up showed sustained tHcy reduction with PFO closure, unlike medical therapy alone; residual shunting correlated with persistent tHcy elevation.
Conclusions:
- PFO shunting is associated with elevated circulatory total homocysteine (tHcy), which is normalized by PFO closure.
- PFO may contribute to stroke via clot-independent mechanisms, potentially mediated by elevated tHcy.
- tHcy serves as a potential cost-effective biomarker for assessing residual shunting and neurovascular risk in PFO stroke patients.
Objective:
To determine the influence of patent foramen ovale (PFO) closure on circulatory biomarkers.
Methods:
Consecutive 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.
Results:
Patients 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).
Conclusions:
PFO 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.
