An integrative model of leukocyte genomics and organ dysfunction in heart failure patients requiring mechanical circulatory support

Abstract

BackgroundThe implantation of mechanical circulatory support (MCS) devices in heart failure patients is associated with a systemic inflammatory response, potentially leading to death from multiple organ dysfunction syndrome. Previous studies point to the involvement of many mechanisms, but an integrative hypothesis does not yet exist. Using time-dependent whole-genome mRNA expression in circulating leukocytes, we constructed a systems-model to improve mechanistic understanding and prediction of adverse outcomes.\n\nMethodsWe sampled peripheral blood mononuclear cells from 22 consecutive patients undergoing MCS surgery, at 5 timepoints: day -1 preoperative, and days 1, 3, 5, and 8 postoperative. Phenotyping was performed using 12 clinical parameters, 2 organ dysfunction scoring systems, and survival outcomes. We constructed a systems-representation using weighted gene co-expression network analysis, and annotated eigengenes using gene ontology, pathway, and transcription factor binding site enrichment analyses. Genes and eigengenes were mapped to the clinical phenotype using a linear mixed-effect model, with Cox models also fit at each timepoint to survival outcomes. Finally, we selected top genes associated with survival across all timepoints, and trained a penalized Cox model, based on day -1 data, to predict mortality risk thereafter.\n\nResultsWe inferred a 19-module network, in which most module eigengenes correlated with at least one aspect of the clinical phenotype. We observed a response to surgery orchestrated into stages: first, activation of the innate immune response, followed by anti-inflammation, and finally reparative processes such as mitosis, coagulation, and apoptosis. Eigengenes related to red blood cell production and extracellular matrix degradation became predictors of survival late in the timecourse, consistent with organ failure due to disseminated coagulopathy. Our final predictive model consisted of 10 genes: IL2RA, HSPA7, AFAP1, SYNJ2, LOC653406, GAPDHP35, MGC12916, ZRSR2, and two currently unidentified genes, warranting further investigation.\n\nConclusionOur model provides an integrative representation of leukocyte biology during the systemic inflammatory response following MCS device implantation. It demonstrates consistency with previous hypotheses, identifying a number of known mechanisms. At the same time, it suggests novel hypotheses about time-specific targets.