*Purpose: It has long been recognized that transplanted hearts develop a stiffened, restrictive physiology at an accelerated rate compared to native hearts. While this is thought to be due to a variety of factors which result in local inflammatory injury and subsequent remodeling. Inflammatory insults and their subsequent effects on in-situ tissue architecture have never been rigorously studied. In this work, we sought to use quantitative image analysis tools to measure a variety of morphologic biomarkers pertaining to collagen changes in a large cohort of endomyocardial biopsy (EMB) samples. We then apply these features to investigate the roles of several potential causes of inflammation (reperfusion injury, quilty lesions, and a history of cellular rejection) in the transplanted heart.

*Methods: Given that the collagen in different regions have different responses to the causes of inflammation, a U-net model was trained to classify collagen into three types according to its location: collagen at the edge of the myocardium, collagen around myocytes, and collagen inside stroma. Collagen fibers were further segmented by utilizing a local binary pattern operator combined with OTSU algorithm. We then extracted a set of 216 biologically-inspired collagen features, relating to the density, morphology, spatial arrangement and interaction with myocytes. The relationship between 216 collagen features and the causes of inflammation were comparatively analyzed. Feature selection was employed to identify the most 5 predictive features on a set of 911 slides and these were subsequently trained with a random forest classifier to predict the existence of the causes of inflammation. The area under the receiver operating characteristic curves (AUCs) were calculated to evaluate the model performance on the test 395 slides.

*Results: 1) The AUCs for predicting the existence of reperfusion injury, quilty lesions, and a history of cellular rejection reached 0.65, 0.61 and 0.81, respectively. This showed that collagen features were strongly linked to the causes of inflammation studied. 2) Different causes of inflammation showed different effects on the three types of collagen; quilty lesion mainly acted on the collagen at the edge of the myocardium, while reperfusion injury mainly acted on the collagen around myocytes. 3) Collagen features were more closely related to the historical rejection grade than the current rejection grade, indicating that the change of collagen features was a gradual accumulation process.

*Conclusions: This work demonstrates that the novel biomarkers derived from collagen are highly potential for the mechanism-exploring of the causes of inflammation in remodeling of the transplanted myocardium.

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