Cardiovascular exercise mitigates reperfusion failure and persistent hypoperfusion in the thrombin model of stroke and thrombolysis

Ischemic stroke remains a significant healthcare challenge, with reperfusion failure - insufficient tissue reperfusion despite successful vessel recanalization - limiting the effectiveness of recanalization treatments. However, mechanisms of reperfusion failure remain elusive, and effective treatments are lacking. This study explored whether early cardiovascular exercise could mitigate reperfusion failure. Using a rat model of ischemic stroke and thrombolysis, treadmill exercise was initiated 2 days post-stroke. Brain perfusion and functional recovery were assessed using MRI, Laser Speckle Contrast Imaging (LSCI) and functional tests. All rats treated with intravenous thrombolysis (IVT) demonstrated successful clot dissolution. However, brain perfusion only recovered to 67.6% ± 8.7% of baseline levels. Hypoperfusion persisted up to 28 days post-stroke (89.9% ± 4.8% of baseline levels). Treadmill exercise significantly mitigated reperfusion failure and chronic hypoperfusion, exhibiting substantial improvements in brain perfusion at 28 days (102.3% ± 1% of baseline levels). This resulted in smaller T2 hyperintense lesion volumes (10.4 ± 8.5 mm³ vs 26.7 ± 21.1 mm³) and enhanced functional recovery. These findings suggest that reperfusion failure transitions into chronic hypoperfusion after stroke, impeding recovery, but may be alleviated by early cardiovascular exercise, which improves vascular resilience and reperfusion recovery following ischemic stroke. Further clinical studies are needed to determine whether similar benefits can be achieved in stroke patients.