Chronic hemodynamic stress drives erythrocyte remodeling in patent foramen ovale

Background

Patent foramen ovale (PFO) is associated with paradoxical embolism, cryptogenic stroke, and migraine with aura. The biomechanical mechanisms underlying these associations remain poorly defined. We previously reported that patients with PFO display reduced erythrocyte count, hemoglobin, and hematocrit, all of which normalize after PFO closure. These findings suggest a possible role for chronic mechanical and oxidative stress in erythrocyte dysfunction.

Purposes

To investigate erythrocyte morphology, deformability, and aggregability in patients with PFO before and six months after PFO closure.

Methods

Sixty-seven patients with PFO were evaluated before and six months after transcatheter PFO closure and compared with 28 healthy subjects (HS). Erythrocyte count and red blood cell distribution width (RDW-CV) were assessed by automated blood count. Erythrocyte morphology was analyzed by transmission electron microscopy (TEM). Erythrocyte deformability under increasing shear stress and aggregability were assessed using laser-assisted optical rotational cell analyzer (LoRRca).

Results

Patients with PFO showed significantly higher RDW-CV compared with HS (13.43% ± 1.36 vs 12.44% ± 0.53; p = 0.0011), a parameter that remained elevated six months after PFO closure (13.82% ± 1.75), consistent with the long lifespan of erythrocytes. TEM analysis revealed, in addition to normal biconcave erythrocytes, a previously undescribed “shield-shaped” erythrocyte morphology observed exclusively in PFO patients (Figure). Functionally, erythrocytes from PFO patients showed reduced deformability under prolonged shear stress compared with post-closure values (elongation index 0.18 ± 0.03 vs 0.20 ± 0.04; p=0.019). Moreover, erythrocyte aggregability was significantly increased before PFO closure and decreased at six-month follow-up (amplitude 36.45 ± 3.66 vs 34.07 ± 3.36; p=0.0002).

Conclusions

Patients with PFO exhibit a distinct erythrocyte phenotype characterized by altered morphology, reduced deformability, and increased aggregability. While erythrocyte mechanical function partially recovers after PFO closure, morphological alterations persist, suggesting chronic erythrocyte remodeling. These findings support a role for PFO-related mechanical stress in erythrocyte dysfunction, potentially contributing to the prothrombotic and vasoactive milieu associated with PFO.

Figure. Ultrastructural analysis of erythrocytes in patients with patent foramen ovale. Transmission electron microscopy reveals heterogeneous erythrocyte morphology in patients with patent foramen ovale, including normal biconcave “disc-shaped” cells and a previously undescribed shield-shaped phenotype. This abnormal morphology was observed exclusively in PFO patients and was not detected in healthy subjects. Scale bar: 10 μm.Ultrastructural analysis of erythrocytesFor image description, please refer to the figure legend and surrounding text.