Interplay of patent foramen ovale and severe obesity in long-term thromboembolic and cardiovascular outcomes

Background The clinical impact of severe obesity on outcomes among patients with patent foramen ovale (PFO), and the incremental risk conferred by PFO among individuals with severe obesity, remain insufficiently quantified in real-world care. Methods Using a global federated electronic health record network (TriNetX), we performed two complementary propensity-score matched (1:1) time-to-event analyses with follow-up from day 1 to day 1825 after index.Analysis A: compared PFO patients with BMI ≥35 versus BMI <35.Analysis B compared BMI ≥35 patients with PFO versus BMI ≥35 patients without PFO. Patients with prior cardiovascular or embolic events were excluded before index. The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCE). Secondary endpoints included stroke and all-cause mortality. A negative-control outcome was assessed to evaluate residual bias. Results In Analysis A, BMI ≥35 was associated with higher 5-year MACCE (13.8% vs 11.9%; HR 1.27, 95% CI 1.08–1.49; p=0.004), stroke (8.8% vs 5.3%; HR 1.57, 1.23–2.00; p<0.001), and all-cause mortality (10.5% vs 9.3%; HR 1.30, 1.06–1.59; p=0.010), while the negative-control outcome was neutral (HR 1.10, 0.74–1.63; p=0.61). Conversely, in Analysis B, PFO was associated with higher MACCE (15.3% vs 9.6%; HR 1.22, 1.07–1.40; p=0.003) and a marked increase in stroke risk (5.8% vs 2.4%; HR 3.20, 2.45–4.17; p<0.001), whereas all-cause mortality was neutral (HR 0.99, 0.88–1.11; p=0.86). The negative-control outcome showed no significant association (HR 0.83, 0.63–1.09; p=0.18). Conclusion Severe obesity amplifies long-term cardiovascular and thromboembolic risk among patients with PFO. Conversely, among individuals with severe obesity, PFO is strongly associated with stroke without increasing overall mortality. Neutral negative-control findings support specificity of the thromboembolic signal.