a-high-fidelity-porcine-model-orthotopic-heart-transplantation

A High-Fidelity Porcine Model of Orthotopic Heart Transplantation Following Donation after Circulatory Death

The number of advanced heart failure patients who can receive a heart transplant is limited by a shortage of suitable organ donors. In efforts to expand ...

Duke University Medical Center

 It may take decades to develop cardiovascular dysfunction following exposure to high doses of ionizing radiation from medical therapy or from nuclear accidents. Since astronauts may be exposed continually to a complex space radiation environment unlike that experienced on Earth, it is unresolved whether there is a risk to cardiovascular health during long-term space exploration missions. Previously, we have described that mice exposed to a single dose of simplified Galactic Cosmic Ray (GCR) develop cardiovascular dysfunction by 12 months post-radiation.  To investigate the biological basis of this dysfunction, here we performed a quantitative mass spectrometry-based proteomics analysis of heart tissue (proteome and phosphoproteome) and plasma (proteome only) from these mice at 8 months post-radiation.  Differentially expressed proteins (DEPs) for irradiated versus sham irradiated samples (fold-change ≥1.2 and an adjusted -value of ≤0.05) were identified for each proteomics data set. For the heart proteome, there were 87 significant DEPs (11 upregulated and 76 downregulated); for the heart phosphoproteome, there were 60 significant differentially phosphorylated peptides (17 upregulated and 43 downregulated); and for the plasma proteome, there was only one upregulated protein. A Gene Set Enrichment Analysis (GSEA) technique that assesses canonical pathways from BIOCARTA, KEGG, PID, REACTOME, and WikiPathways revealed significant perturbation in pathways in each data set. For the heart proteome, 166 pathways were significantly altered (36 upregulated and 130 downregulated); for the plasma proteome, there were 73 pathways significantly altered (25 upregulated and 48 downregulated); and for the phosphoproteome, there were 223 pathways significantly affected at 0.1 adjusted -value cutoff. Pathways related to inflammation were the most highly perturbed in the heart and plasma. In line with sustained inflammation, neutrophil extracellular traps (NETs) were demonstrated to be increased in GCR irradiated hearts at 12-month post irradiation. NETs play a fundamental role in combating bacterial pathogens, modulating inflammatory responses, inflicting damage on healthy tissues, and escalating vascular thrombosis.  These findings suggest that a single exposure to GCR results in long-lasting changes in the proteome and that these proteomic changes can potentiate acute and chronic health issues for astronauts, such as what we have previously described with late cardiac dysfunction in these mice.

Proteomic and phosphoproteomic characterization of cardiovascular tissues after long term exposure to simulated space radiation.

Outflow graft obstruction (OGO) is an under-reported but severe complication after insertion of magnetically levitated centrifugal-flow left ventricular assist devices (LVADs). The optimal treatment and long-term outcomes have not been well-described. We report a retrospective single high-volume center's experience with surgical exploration for OGO from June 2019 to October 2023. Outflow graft obstruction was identified in 19 LVAD recipients from a total experience of 550 LVAD implants (3.3%). Median time of LVAD support to development of OGO was 32.5 months (interquartile range [IQR], 28-47.5). Low-flow alarms were the most common presentation, followed by dyspnea on exertion, and syncope. Computed tomography angiography (CTA) and echocardiography were the most common diagnostic modalities. Aortic valve opening with every beat and worsened mitral insufficiency were both more common at presentation compared to prior echocardiographic studies. Surgical excision of the bend relief (BR) and evacuation of proteinaceous material between the BR and the outflow graft immediately improved hemodynamics and LVAD function. There were no in-hospital mortalities, and all patients were discharged home after a median length of stay of 9 days (IQR, 10-21). All but four patients were alive at median follow-up 21 months. Thirteen of the 19 patients were readmitted a total of 50 times, none for recurrent OGO.

Article	Year
Proteomic and phosphoproteomic characterization of cardiovascular tissues after long term exposure to simulated space radiation. Frontiers in physiology\| PubMed ID: 38699144	2024
Surgical Intervention for Outflow Graft Obstruction in Patients With Magnetically Levitated Centrifugal-Flow Left Ventricular Assist Devices. ASAIO journal (American Society for Artificial Internal Organs : 1992)\| PubMed ID: 40047264	2025

Alejandro A. Lobo

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