Molecular and Cellular Pathways of Inflammation in the Pre- and Post-Cardiotomy Pericardial Space

Abstract

To date, little attention has been given to the pericardial space as it has merely been considered a simple sac that protects the heart. The contents of the pericardial space include pericardial fluid. Supporting the clinical importance of pericardial fluid, preclinical research has shown that its removal contributes to pericardial adhesion formation – suggesting that pericardial fluid contains biologically important factors. Furthermore, while systemic markers of cardiovascular diseases have been extensively studied, data on the local microenvironment is sparse. Specifically, our understanding of the pericardial immune microenvironment and its potential dynamism in response to myocardial injury and cardiac surgery has been limited. The overall objectives of this Thesis are to 1) Describe the immune profile of native human pericardial fluid, 2) Determine whether myocardial injury and surgical manipulation can affect the composition of pericardial inflammatory mediators, and 3) Assess the pro- and anti-fibrotic capacity of pericardial components. These objectives aim to provide insight into a space that can be leveraged for its diagnostic, prognostic, and therapeutic potential. To address these objectives, we employ various approaches including in vitro, in vivo, and in silico models. The Thesis is developed on the foundation of manuscripts. It can be conceptualized under two major categories: 1) assessment of the native pericardial milieu in setting of ischemic and non-ischemic heart disease, and 2) evaluation of the pericardial space after cardiac surgery. Encapsulated within these two themes are a total of fifteen chapters. The first four chapters are Review Manuscripts that establish the clinical relevance of the first theme. The fifth chapter utilizes a porcine model to evaluate the impact acute myocardial injury has on the pericardial immune profile. The sixth chapter provides a description of human pericardial fluid immune cell composition after myocardial infarction. The seventh, eighth, ninth chapters offer an in-depth analysis of the functional role of human pericardial fluid components. The second theme of the Thesis begins with chapter ten, which is a Review Manuscript that sets the stage for postoperative implications of pericardial inflammatory markers. Chapters eleven, twelve, and thirteen are also Review Manuscripts that further expand on the importance of the postoperative pericardial environment with respect to clinical metrics. Finally, chapters fourteen and fifteen demonstrate how the pericardial inflammatory profile evolves after cardiac surgery.