Extracellular matrix and cytoskeletal reverse remodeling pathways are key drivers of myocardial recovery following left ventricular assist device therapy

SHANKAR, T. S.; Marchetti, M.; Srinivasan, H.; Visker, J. R.; Hamouche, R.; Johnson, E.; Jeong, J.; Kyriakoulis, I.; Ling, J.; Sideris, K.; Selzman, C. H.; Hernandez, E. J.; Tristani-Firouzi, M.; Tseliou, E.; Drakos, S. G.; Wever-Pinzon, O.

doi:10.1101/2025.11.06.687098

bioRxiv · 10.1101/2025.11.06.687098

Extracellular matrix and cytoskeletal reverse remodeling pathways are key drivers of myocardial recovery following left ventricular assist device therapy

SHANKAR, T. S.·Marchetti, M.·Srinivasan, H.·Visker, J. R.·Hamouche, R.·Johnson, E.·Jeong, J.·Kyriakoulis, I.·Ling, J.·Sideris, K.·Selzman, C. H.·Hernandez, E. J.·Tristani-Firouzi, M.·Tseliou, E.·Drakos, S. G.·Wever-Pinzon, O.

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Abstract

Transcriptomic changes in heart failure (HF) patients prior to and following left ventricular assist device (LVAD) support have been extensively studied. Recent studies focused on understanding DNA methylation changes in patients with cardiovascular diseases (CVD) and the role of circulating markers of DNA methylation as clinical predictors of the risk of CVD related morbidity and mortality. In this study, we used paired (pre- and post-LVAD) myocardial samples to examine changes in DNA methylation alongside RNA and protein expression. Our data suggests that patients with no improvement in cardiac function after LVAD therapy, despite showing an improvement in energy production (increased {beta}-oxidation of fatty acid) exhibited persistent activation of profibrotic signaling, increased collagen deposition and cytoskeletal disarray evident from abnormal increase in sarcomeric distance following LVAD support. Contrarily, patients with improvement in cardiac function after LVAD therapy showed activation of pro-inflammatory signaling, collagen degradation and myogenesis. Both RNA sequencing and western blot data showed increased COL1A1 and decreased TPPP3 in post-NR thereby suggesting increased fibrosis and disrupted cytoskeletal signaling as potential barriers to myocardial recovery. Additionally, responders to LVAD therapy showed a significant reversal in myocardial interstitial fibrosis with a preserved sarcomeric architecture. Mice model of HF and recovery also confirmed our human findings, with reduced fibrotic signaling and improved cytoskeletal remodeling signaling observed in mice that showed improvement in cardiac function compared to mice with HF. Overall, our data suggests that altering extracellular matrix regulation and cytoskeletal signaling pathways may contribute to myocardial recovery. Further studies targeting these pathways are required to identify new HF therapeutic targets.

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SHANKAR, T. S., Marchetti, M., Srinivasan, H., Visker, J. R., Hamouche, R., Johnson, E., Jeong, J., Kyriakoulis, I., Ling, J., Sideris, K., Selzman, C. H., Hernandez, E. J., Tristani-Firouzi, M., Tseliou, E., Drakos, S. G., Wever-Pinzon, O.. 2025-11-08. Extracellular matrix and cytoskeletal reverse remodeling pathways are key drivers of myocardial recovery following left ventricular assist device therapy. https://doi.org/10.1101/2025.11.06.687098

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