Transcriptomic Signatures of Right Ventricular Dysfunction and Systemic Complications in Advanced Heart Failure

Abstract

Background: Heart failure (HF) is a complex syndrome where clinical stratification has historically relied on hemodynamic parameters, often overlooking the distinct molecular profile of the Right Ventricle (RV). Methods: This study used a multi-stage design, interrogating 109 human heart tissue samples (CAGE-seq) and validating findings in 29 Peripheral Blood Mononuclear Cell (PBMC) profiles from patients undergoing Mechanical Circulatory Support (MCS). Results:  We identified robust correlations between gene expression and clinical phenotypes. Specifically, the lymphatic marker LYVE1 showed a strong positive correlation with the MELD-XI score (r=0.64, p<0.01) and the SOFA score (r=0.39, p=0.041), linking lymphatic activation to congestive hepatopathy. In the RV, TIMP4 expression was significantly higher in patients with moderate-to-severe dysfunction compared to mild cases (ANOVA p=0.041), also correlating with RV dimensions (r=0.40, p<0.05)4. A collagen switch was observed where COL21A1 correlated with adverse outcomes (r=0.26) while COL24A1 was protective. Furthermore, in patients with preserved RV function, elevated CDK1 was a significant predictor of 1-year mortality (p=0.024), serving as a hidden signal of cellular failure. Finally, IL12A showed significant upregulation in females compared to males (p=0.035), suggesting sex-specific inflammatory pathways.  Conclusions:  These findings offer a biologically relevant framework for monitoring and treating the systemic complications of HF which may be stratified at a molecular level.