H Heymer (1,2), N Hornaschewitz (1,2), M Corsten (1,2), L Xianghai (1), E Wolf (3), A Parzefall (4), N Klymiuk (1,2), C Kupatt (1), A Baehr (1,2)

1: Department of Internal Medicine I, Klinikum rechts der Isar, TU Munich, Germany; 2: Center for Innovative Medical Models; LMU Munich, Germany; 3: Chair for Molecular Animal Breeding and Biotechnology, LMU Munich, Germany; 4: Institute for Veterinary Pathology, LMU Munich, Germany

Background

Scar formation during myocardial remodelling after ischemia/reperfusion (I/R) is intricately regulated by the immune system. The fusion protein LEA29Y is an immunosuppressive medication that inhibits T-cell co-stimulation, limiting immune cell activation. A pig model with systemic LEA29Y expression has been established to investigate I/R injury and remodelling under immunocompromised conditions, including a focus on collagen content as a marker of scar formation and quantifying immune cells.

Methods

Using a catheter-based intervention, 60 minutes of ischemia in the LAD was induced, followed by permanent reperfusion, resulting in infarction in the left ventricle (LV). Animals were sampled after 3, 9, 14, and 26 days and compared to controls. Ejection fraction was calculated, ECG recorded, and histological stainings performed with HE, Sirius Red, IBA1, CD3-T-Cells, and neutrophils. Histological analysis was conducted using “QuPath” for high-resolution global measurement of stained tissue.

Results

LEA29Y and wild-type (WT) animals displayed similar infarct sizes. LV angiography showed a significantly higher loss of ejection fraction in transgenic pigs after 3 days (-15.48±1.069 vs. -7.554±1.873, p=0.011). QuPath analysis revealed a peak of collagen at day 14, with a slower decrease to day 26 in LEA29Y animals compared to WT (day 14: 18.4% LV LEA29Y vs. 20.75% LV WT; day 26: 16.49% LV LEA29Y vs. 15.04% LV WT).

Conclusion

Blocking T-cell co-stimulation leads to greater initial loss of LV function and delayed scar contraction. Further immunohistochemical studies will explore T-cell loss and interactions with other immune cells, enhancing understanding of the physiological impact of immunosuppression after I/R.