Multidimensional Molecular Biomarkers of MultiOrgan Dysfunction after MCS Therapy

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DESCRIPTION (provided by applicant): Heart failure (HF) affects nearly 6 million people in the United States. Currently, Mechanical Circulatory Support Device (MCS) therapy is the only alternative for patients with advanced heart failure (AdHF) who are not candidates for heart transplantation. MCS is increasingly being offered to highly complex patients with AdHF and multiple comorbidities. Multiple abnormal immune functions describe the AdHF syndrome and the critically ill patient. Despite being life-saving, inflammatory mechanisms may put patients at risk of developing multiorgan dysfunction syndrome (MOD) characterized by persistent activation of the systemic inflammatory response, decreased organ perfusion and end organ damage. We propose that the interaction between altered leukocyte and endothelial cell biology in hypoperfused organs and tissues worsen organ dysfunction and activate the immune system, leading to uncontrolled systemic inflammatory response and MOD, the most common cause of death among patients with AdHF after MCS surgery. Microarray technologies allowed the implementation of genome wide molecular diagnostics. Integrative genomics and systems biological methodologies set the basis to develop a new generation of molecular tools as robust biomarkers. Flow cytometry is a robust methodology that allows for the characterization of many subsets of cells in a complex mixture such as blood by identifying cell-surface proteins, intracellular phosphoproteins and cytokines, as well as other functional readouts. Research by our group identified patterns of inflammatory response after MCS assessed by peripheral blood mononuclear cell (PBMC) gene expression that are directly and specifically related to increasing degrees of MOD. Our hypothesis is that multidimensional molecular biomarkers (MMB) improve the evaluation and selection of patients undergoing MCSD who are at risk of MOD. MMBs incorporate multi-parameter immune cell flow cytometry, and genome wide transcriptome analysis using RNA Sequencing evaluated in a time- dependent design using systems-based computational analysis. To test our hypothesis, we will conduct a prospective time-dependent study in MCS recipients designed to characterize (1) temporal patterns of PBMC gene expression and (2) temporal patterns of PBMC immune phenotypes after MOD to (3) reconstruct the temporal gene expression - immunophenotype program of MOD after MCS and (4) test the feasibility and preliminary efficacy of MMB to predict the risk of MOD after MCS. Discoveries made by this proposal will lead to novel molecular biomarker development for the improved evaluation of complex phenotypes and risk prediction in AdHF patients being selected for MCS.