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Heart failure has a poor prognosis and no curative treatment exists. Clinical trials are investigating gene- and cell-based therapies to improve cardiac function. The safe and efficient delivery of these therapies to solid organs is challenging. Herein, we demonstrate the feasibility of using an endovascular intramyocardial delivery approach to safely administer mRNA drug products and perform cell transplantation procedures in swine. Using a trans-vessel wall (TW) device, we delivered chemically modified mRNAs (modRNA) and mRNA-enhanced mesenchymal stromal cells expressing vascular endothelial growth factor A (VEGF-A) directly to the heart. We monitored and mapped the cellular distribution, protein expression, and safety tolerability of such an approach. The delivery of modRNA-enhanced cells via the TW device with different flow rates and cell concentrations marginally affect cell viability and protein expression in situ. Implanted cells were found within the myocardium for at least 3 days following administration, without the use of immunomodulation and minimal impact on tissue integrity. Finally, we could increase the protein expression of VEGF-A over 500-fold in the heart using a cell-mediated modRNA delivery system compared with modRNA delivered in saline solution. Ultimately, this method paves the way for future research to pioneer new treatments for cardiac disease.
RESUMO
BACKGROUND: The aim of this study was to assess the eventual added benefit of antigranulocyte monoclonal antibodies scintigraphy for the diagnostic imaging of aortic graft infection (AGI) and its role in evaluation of treatment outcome. METHODS: A population-based, retrospective, register-based analysis was carried out of all patients with infected aortic grafts after treatment for aneurysmal or aortoiliac occlusive disease at Karolinska University Hospital, covering the greater Stockholm area during November 2012-December 2020. Cases were based on the definitions in the 2016 Management of Aortic Graft Infection Collaborations consensus. Using the in-hospital electronic patient registry (Take Care®) and the Swedish National Registry for Vascular Surgery (Swedvasc), 835 patients who had been treated for aortic aneurysms or aortoiliac occlusive disease were identified. The diagnostic arsenal of laboratory tests, computed tomography (CT), and clinical signs has been supplemented by antigranulocyte monoclonal antibodies (anti-G mAb) scintigraphy. Data were analyzed using SPSS Statistics. RESULTS: Eighteen cases of AGI out of 835 operations incorporating aortic grafts during the period were identified. Fourteen patients (78%) were categorized as diagnosed AGI (AGI-D), and the remaining 4 (22%) were classified as suspected AGI (AGI-S). In the AGI-D group (n = 14), 10 patients (71%) had positive CTs and 4 (29%) had low-probability CTs. In the group of 10 positive CTs, 9 patients also had positive scintigraphy scans with only one negative scintigraphy scan. There were no negative scintigraphy scans without ongoing antibiotic treatment at the time of investigation. In 15 of 18 cases, a culprit agent was identified, either preoperatively or perioperatively. Thirteen of the 18 patients were treated solely by antibiotics, whereas 5 underwent surgical treatment in addition to antibiotic treatment. The outcome has been divided into 3 groups: infection-free (n = 6; 33%), lifelong antibiotic treatment (n = 7; 39%), and deceased (n = 5; 28%). CONCLUSIONS: The imaging modalities in AGI diagnostics are a cornerstone of the investigative work-up, complemented by clinical signs and laboratory methods. The main advantage conveyed by anti-G mAb scintigraphy is in postoperative imaging and its ability to differentiate between infection and general postoperative changes in the areas of concern. We have identified 6 patients in our cohort in whom antibiotic therapy was discontinued after a negative anti-G mAb scintigraphy scan. Anti-G mAb scintigraphy may fulfill a unique need for diagnosis in suspected cases, evaluation of therapeutic efficacy in patients requiring long-term antibiotic treatment, and aiding in the decision to discontinue antibiotic therapy.