Association between preoperative peripheral blood mononuclear cell gene expression profiles, early postoperative organ function recovery potential and long-term survival in advanced heart failure patients undergoing mechanical circulatory support v1

Background: Multiorgan dysfunction syndrome (MOD) contributes to adverse outcomes in advanced heart failure (AdHF) patients after mechanical circulatory support (MCS) implantation and is associated with aberrant leukocyte activity. We tested the hypothesis that preoperative peripheral blood mononuclear cell (PBMC) gene expression profiles (GEP) can predict early postoperative improvement or non-improvement in patients undergoing MCS implantation and that this information might be used to develop long-term prognostic biomarkers. Methods & Design: We conducted a time series study with 29 patients undergoing MCS-surgery in a Tertiary Academic Medical Center between August 2012 – 2014. The patients were classified into two clinically relevant organ failure risk strata by Sequential Organ Failure Assessment (SOFA) and Model of End-stage Liver Disease Except INR (MELD-XI) scores, which was measured eight days after surgery: Group I = IMPROVING (both scores improved from day -1 to day 8) and Group II = NOT IMPROVING (either one or both scores did not improve from day -1 to day 8). Clinical data and PBMC samples were collected one day before surgery (day -1), and at days 1, 3, 5 and 8 postoperatively. RNA-sequencing was performed on purified mRNA (Illumina HiSeq 2500 NGS) and analyzed using NGS Strand (Avadis NGS 1.5). Differentially expressed genes (DEGs) were identified by Mann-Whitney test with Benjamini-Hochberg correction (false discovery rate, FDR, < 0.1). Preoperative DEGs with a fold change of at least 2 were used to train a support-vector machine (SVM) algorithm to predict Group I vs. Group II membership. The model was then tested by random subsampling. Main Results: Out of 29 undergoing MCS-surgery patients, 17 were in Group I and 12 in Group II. Out of 28 MCS-surgery patients alive 8 days postoperatively, one-year survival was 88% in Group I and 27% in Group II (log rank p=0.00182). We identified 28 DEGs (FDR<0.1) between Group I and Group II preoperatively, which displayed an average prediction accuracy of 93%. Out of 105 DEGs identified preoperatively between year 1 survivors and non-survivors, 12 genes overlapped with the 28 predictive genes. Conclusions: In AdHF patients following MCS implantation, preoperative PBMC-GEP predicts early changes in organ function scores and correlates with long-term outcomes. These result show that gene expression lends itself to outcome prediction and warrants further studies in larger longitudinal cohorts.