Summary: The molecular mechanisms of right ventricular (RV) adaptation to stress and failure in end stage heart failure (HF) are largely unknown. In this study, we performed transcriptomic analysis on paired RV and left ventricular (LV) myocardial samples from 33 subjects with AHA stage D HF referred for transplantation, and 8 controls who provided donor hearts not ultimately used for transplantation. We categorized patients by RV function - defining failure by Pulmonary Artery Pulsatility Index <1.85 - into control (n=8), compensated (n=25), and failing groupings (n=8). Our analysis found dysregulation of extracellular matrix remodeling, fatty acid metabolism, mitochondrial function, and inflammation in the stressed RV (comparing compensated and failing RVs to controls), implicating similar molecular mechanisms to those identified from studies of pre-capillary pulmonary hypertension (PH) associated RV dysfunction. The compensated and failing RVs were differentiated by protein production/processing and inflammation. PPAR signaling and fatty acid metabolism were consistently enriched in the RV compared to the LV. We also examined 16 previously proposed transcriptional biomarkers of RV failure, finding that none effectively differentiated between RV compensation and failure, and only 4 were RV-specific (changing in RV-failure but not LV-failure). Our findings suggest that the molecular mechanisms of pre-capillary PH and HF-associated RV dysfunction exhibit significant overlap. Furthermore, fatty acid metabolism and related signaling may be constitutively different between the RV and LV in both normal function and failure.

The authors have declared no competing interest.

This research was supported by the National Heart Lung and Blood Institute: T32 HL 087738 (Garry), U01 HL125212-01 (Hemnes), R01 HL155289 (Brittain), R34 HL173389 (Brittain), R61/R33 HL 158941 (Brittain), R01 HL163960 (Brittain), R01 HL146588 (Brittain), the US Food and Drug Administration R01 FD007627 (Brittain, Hemnes), American Heart Association Strategically Focused Research Network (SFRN) grant 18SFRN34110369 (Davogustto), and Veterans Affairs Career Development Award IK2BX005828 (Agrawal).

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The Institutional Review Board of Vanderbilt University Medical Center gave ethical approval for this work.

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