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Reconnecting Vagus Nerve to the Heart through Nerve Conduit Preserves Cardiac Function in a Minipig Model of Right Cardiac Vagotomy

ABSTRACT: The right vagus nerve (RVN) plays a crucial role in maintaining cardiac homeostasis, and its intrathoracic resection leads to postoperative cardiac complications. Developing effective method to repair the RVN after surgical transection at the heart level is a critical unmet clinical need. Here we show that early reconnection of the RVN to the heart promoted by implantable Chitosan/Poly-e-caprolactone cuff-like nerve guidance conduit (ChiPCL. C-NGC) significantly preserves cardiac mechanical function in minipigs subjected to right cardiac vagotomy (RVT). Animals that were randomly treated with ChiPCL. C-NGC showed improved global circumferential, longitudinal, and radial strain, along with reduced diastolic dyssynchrony. Histopathology revealed 20% viable vagal fascicles, normalized levels of myocardial parasympathetic fibers, oxidative stress- and aging-related markers, and prevented interstitial myocardial fibrosis in treated group. Our findings suggest that preserving a limited number of RVN fascicles and their neurofilaments prevents early cardiac remodeling by lowering oxidative stress-mediated premature senescence of cardiac cells. Reconnecting the RVN to the heart via ChiPCL C-NGC presents a potential therapeutic strategy to prevent RVT-induced heart failure following thoracic surgery or heart and lung transplantation

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Sus Scrofa (ncbitaxon:9823)

SUBMITTER: Alessandro Cellerino

PROVIDER: MSV000099384 | MassIVE | Sun Oct 05 06:35:00 BST 2025

SECONDARY ACCESSION(S): PXD069137

REPOSITORIES: MassIVE

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Project description:Background Sunitinib is a small molecule tyrosine kinase inhibitor approved for the treatment of diverse cancers. Despite widespread clinical approval the associated cardiovascular toxicity sequelae are of concern; high grade toxicities may lead to dose reduction, interruption or discontinuation. Thus, an effective strategy for the early detection of cardiac damage in the context of sunitinib treatment is warranted. Although yet to be fully elucidated, molecular pathways and kinases implicate include those related to cardiac energy metabolism. We hypothesised that plasticity in cardiac metabolism could represent a novel early marker of cardiotoxicity. Methods and Results Female Balb/CJ mice (n = 36) or Sprague-Dawley rat (n = 12) models were treated with sunitinib. Physiological parameters were measured. An hypothesis driven cardiac positron emission tomography (PET) approach was implemented to investigate alterations in myocardial glucose, fatty acid and oxidative metabolism. Following treatment, blood pressure increased, whilst left ventricular ejection fraction decreased in both models. Increased myocardial glucose uptake after 48 hours indicated early perturbations in glucose metabolism. Myocardial fatty acid metabolism appeared increased as a result of sunitinib treatment indicated by PET but electron microscopy revealed significantly increased storage of lipids in the myocardium. Proteomic analyses indicated that oxidative metabolism, fatty acid β-oxidation and mitochondrial dysfunction were among the top cardiac signalling pathways perturbed by sunitinib treatment. [11C]Acetate-PET data suggested a decrease in myocardial perfusion following 5 days of treatment. Conclusions Data implicates sunitinib as a mediator of compromised myocardial energy metabolism. Increased reliance on glycolysis, increases in myocardial lipid deposition and perturbed mitochondrial function may ultimately result in a fundamental energy crisis manifesting as compromised cardiac function, the long term effects of which are unknown. Our data support the utility of an hypothesis driven PET approach to monitor cardiac metabolic pathway remodelling in response to sunitinib, which may ultimately have clinical utility as a novel safety imaging biomarker strategy.

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Reconnecting Vagus Nerve to the Heart through Nerve Conduit Preserves Cardiac Function in a Minipig Model of Right Cardiac Vagotomy

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