Proteomic remodeling of the heart following transplantation: the signature of cardiac allograft vasculopathy

The major detriment to long-term survival with a transplanted heart is cardiac allograft vasculopathy (CAV). The molecular pathophysiology of CAV is poorly understood. Once CAV is diagnosed, treatment is ineffective, but early (preangiographic) detection would enable a more timely treatment strategy. The aim of the study is to investigate the early changes in the heart proteome following a transplantation and to identify differences associated with CAV development.

As part of routine clinical care following heart transplantation, the graft is monitored by collecting endomyocardial biopsies at defined time points. These are currently evaluated by histology, but some formalin-fixed and paraffin-embedded (FFPE) tissue remains, enabling research into new diagnostic strategies. We have established a state-of-the-art workflow to perform deep quantitative proteomics measurements from cardiac FFPE samples on a timsTOF HT instrument (diaPASEF). To appropriately analyze proteomics data with repeated measurements taken from the same subject, we have implemented a regression strategy using a linear mixed model with an unstructured covariance pattern for data analysis.

We identified more than 5000 unique proteins across 200 endomyocardial biopsies, corresponding to 40 patients and 5 time points per patient. We observed a substantial change in the proteome over time as the graft adapts to its new environment in the transplant recipient. Notably, we identified proteins associated with the development of CAV.

This study adds to the understanding of the early adaptation of a transplanted human heart and could potentially lead to identification of biomarkers for early CAV detection.