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Comparative Study of Human and Murine Aortic Biomechanics and Hemodynamics in Vascular Aging

ABSTRACT: Introduction: Aging has many effects on the cardiovascular system, including changes in structure (aortic composition, and thus stiffening) and function (increased proximal blood pressure, and thus cardiac afterload). Mouse models are often used to gain insight into vascular aging and mechanisms of disease as they allow invasive assessments that are impractical in humans. Translation of results from murine models to humans can be limited, however, due to species-specific anatomical, biomechanical, and hemodynamic differences. In this study, we built fluid-solid-interaction (FSI) models of the aorta, informed by biomechanical and imaging data, to compare wall mechanics and hemodynamics in humans and mice at two equivalent ages: young and older adults. Methods: For the humans, 3-D computational models were created using wall property data from the literature as well as patient-specific magnetic resonance imaging (MRI) and non-invasive hemodynamic data; for the mice, comparable models were created using population-based properties and hemodynamics as well as subject-specific anatomies. Global aortic hemodynamics and wall stiffness were compared between humans and mice across age groups. Results: For young adult subjects, we found differences between species in pulse pressure amplification, compliance and resistance distribution, and aortic stiffness gradient. We also found differences in response to aging between species. Generally, the human spatial gradients of stiffness and pulse pressure across the aorta diminished with age, while they increased for the mice. Conclusion: These results highlight key differences in vascular aging between human and mice, and it is important to acknowledge these when using mouse models for cardiovascular research.

SUBMITTER: Hopper S

PROVIDER: S-EPMC8573132 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAortic dissection (AD) poses a great threat to the life of patients; however, there is currently no documentation of a clear pathogenic mechanism of this disease. In recent years, β-aminopropionitrile (BAPN)-induced AD in rodents has been widely used in basic research, which provides a good platform for exploring the pathogenesis of AD and drug modification. This study aimed to identify molecular markers and pathways for the diagnosis and treatment of AD by comparing a murine AD model and human AD transcriptome through a bioinformatics analysis.MethodsWe constructed a BAPN-induced mice model and performed high-throughput sequencing analysis. The GSE147026 dataset of patients was obtained from the Gene Expression Omnibus database. We performed a subsequent bioinformatics analysis of human AD and the murine AD model using R software. The DESeq software package was used to analyze the differentially expressed genes (DEGs). Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to analyze the enrichment pathways. Protein-protein interaction network construction and hub gene selection were based on STRING software analysis. Stepwise identification of potential drugs was performed online, while hub genes were validated immunohistochemically.ResultsWe compared the murine AD model and human AD transcriptome and found that both differentially expressed 463 genes. The cytokine-cytokine receptor interaction, tuberculosis, and phagosome pathways were significantly enriched. CDC20, CCNB2, and CCNB1 may be associated with AD development. Protein-drug interactions were also identified.ConclusionsThis study is the first to reveal transcriptional changes in a murine BAPN-induced AD model versus human AD transcriptome. Furthermore, we identified the important hub genes, related pathways, and potential drugs by analyzing the overlapping DEGs between human AD and the murine AD model. Our results provide a basis for the further identification of potential molecular markers for diagnosing and treating AD.

Project description:Background and purposeIron chelation therapy is emerging as a novel neuroprotective strategy. The mechanisms of neuroprotection are diverse and include both neuronal and vascular pathways. We sought to examine the effect of iron chelation on cerebrovascular function in healthy aging and to explore whether hypoxia-inducible transcription factor-1 activation may be temporally correlated with vascular changes.MethodsWe assessed cerebrovascular function (autoregulation, vasoreactivity, and neurovascular coupling) and serum concentrations of vascular endothelial growth factor and erythropoietin, as representative measures of hypoxia-inducible transcription factor-1 activation, during 6 hours of deferoxamine infusion in 24 young and 24 older healthy volunteers in a randomized, blinded, placebo-controlled cross-over study design. Cerebrovascular function was assessed using the transcranial Doppler ultrasound. Vascular endothelial growth factor and erythropoietin serum protein assays were conducted using the Meso Scale Discovery platform.ResultsDeferoxamine elicited a strong age- and time-dependent increase in the plasma concentrations of erythropoietin and vascular endothelial growth factor, which persisted ≤3 hours post infusion (age effect P=0.04; treatment×time P<0.01). Deferoxamine infusion also resulted in a significant time- and age-dependent improvement in cerebral vasoreactivity (treatment×time P<0.01; age P<0.01) and cerebral autoregulation (gain: age×time×treatment P=0.04).ConclusionsDeferoxamine infusion improved cerebrovascular function, particularly in older individuals. The temporal association between improved cerebrovascular function and increased serum vascular endothelial growth factor and erythropoietin concentrations is supportive of shared hypoxia-inducible transcription factor-1-regulated pathways. Therefore, pharmacological activation of hypoxia-inducible transcription factor-1 to enhance cerebrovascular function may be a promising neuroprotective strategy in acute and chronic ischemic syndromes, especially in elderly patients.Clinical trial registrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT013655104.

Project description:BackgroundThe durability of transcatheter aortic valves (TAVs) remains their greatest disadvantage, given that fixed tissue leaflets are not immune to structural degeneration from calcification and thrombosis. Therefore, a second intervention is necessary, especially given that TAV in low-risk patients has shown noninferior outcomes compared with surgery. This study aimed to assess the hemodynamic and turbulent properties of the flow downstream with different TAV-in-TAV configurations, to offer basic hemodynamic guidance for future interventions when currently implanted valves structurally degrade.MethodsSix TAV-in-TAV configurations were chosen: 23 mm Evolut-in-26 mm Evolut, 23 mm Evolut-in-23 mm SAPIEN 3, 26 mm Evolut-in-26 mm Evolut, 26 mm Evolut-in-23 mm SAPIEN 3, 23 mm SAPIEN3-in-26 mm Evolut, and 23 mm SAPIEN3-in-23 mm SAPIEN 3. Their hemodynamic performance was assessed in a pulse duplicator for 100 cycles. High-speed imaging and particle image velocimetry were performed to assess turbulence. Effective orifice area (EOA), pinwheeling index (PI), and Reynolds shear stress (RSS) were evaluated.ResultsThe largest mean EOA was obtained with 23 mm SAPIEN-in-26 mm Evolut (2.07 ± 0.06 cm2), and the smallest was obtained with 23 mm Evolut-in-23 mm SAPIEN (1.50 ± 0.04 cm2) (P < .001). The highest mean PI was obtained with SAPIEN-in-SAPIEN (26.5 ± 2.00%), and the lowest was obtained with 26 mm Evolut-in-26 mm Evolut (7.5 ± 1.6%) (P < .01). At peak systole, the least detrimental RSS range was obtained with 23 mm Evolut-in-26 mm Evolut (up to ∼340 Pa), and the most detrimental RSS range was obtained with 23 mm Evolut-in-SAPIEN (∼900 Pa) (P < .01).ConclusionsThis study shows that best hemodynamic parameters are TAV-specific (implanted and to be implanted). In addition, it shows that RSS levels, which are indicative of turbulence levels and associated with blood damage, are 2- to 3-fold higher after TAV-in-TAV.

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Comparative Study of Human and Murine Aortic Biomechanics and Hemodynamics in Vascular Aging

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