Abstract A095: PFO shunting may contribute to cerebral white matter disease via circulatory homocysteine

Background: We previously found patent foramen ovale (PFO) stroke patients may have increased white matter hyperintensities (WMH) and that PFO shunting raises blood homocysteine (bHcy) which can injure brain tissue in vitro. While emerging evidence suggests cardiac shunting may augment brain injury via clot independent pathway, it remains unclear how PFO can cause brain injury besides embolic strokes. In this pilot study, we hypothesized that elevated bHcy level may be a culprit for WMH in PFO patients. Method: 231 PFO patients were prospectively recruited in accordance to IRB protocol. WMH burden was evaluated on MRI by investigators blinded to clinical outcome, and WMH severity was quantified by validated Fazekas and Scheltens scales. Regression and mediation analysis were performed. Result: Consistent with our previous findings, circulating bHcy levels in PFO patients increased proportionally with their shunt size (β: 1.14; 95% CI: 0.45 ~ 1.82; p = 0.001) ( Figure 1A ). Elevated bHcy was strongly associated with greater WMH burden (Fazekas, OR: 1.14; 95% CI: 1.06 ~ 1.21; p < 0.001; Scheltens, OR: 1.15; 95% CI: 1.08 ~ 1.23; p < 0.001) ( Figure 1B, 1C ). PFO shunt itself was associated with WMH (Fazekas, OR: 1.58; 95% CI: 1.16 ~ 2.14; p = 0.004; Scheltens, OR: 1.74; 95% CI: 1.29 ~ 2.35; p < 0.001) ( Figure 1D ), which was particularly evident in deep white matter region ( Figure 1E ). Notably, mediation analysis confirmed a mediating role of bHcy ( Table 1 ). bHcy exhibited significant indirect effect, mediating 19~22% of the effect of PFO on WMH ( Figure 1F ). These results remained robust after accounting for age, a well-known risk factor of bHcy elevation WMH ( Table 1 ). Conclusion: Our pilot results suggest that PFO shunting may contribute to WMH by promoting bHcy elevation. This effect is shunt-size dependent and most pronounced in deep white matter. These preliminary findings provide new insight into PFO shunt related brain injury. Further studies are warranted to understand the underlying mechanism and assess whether cardiac shunt elimination or bHy lowering may impact PFO related white matter disease.