Raman microspectroscopy as a useful new tool in understanding thoracic aortic aneurysms.

Raman spectroscopy is a well-understood technology with novel applications in both research and clinical settings. In their article, Sugiyama and colleagues apply this technology to understand thoracic aortic aneurysm development and biomarker identification.1.

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Thoracic aortic aneurysms (TAAs) have an incidence of 5–10 per every 100,000 person-years, with 60% involving the aortic root or ascending aorta. Untreated TAAs can lead to dissection and/or rupture, both of which pose immediate threat to life and carry a high mortality rate. Ascending TAAs are most often discovered incidentally with cross-sectional imaging or through screening mechanisms for high-risk patients. Despite the identification of heritable forms of TAA linked to specific genetic mutations, much of the underlying etiology of ascending aortic disease remains unknown. In this issue of Cell Reports Medicine, Sugiyama and colleagues report the use of Raman spectroscopy to study the cellular and molecular structure of the aortic wall in both mouse models of TAA and human TAA tissues to shed light on the underlying pathobiology of TAA.

Though the theory behind Raman spectroscopy is nearly 100 years old, its utility for research and clinical applicability has only recently become understood. Raman spectroscopy allows for relatively inexpensive, non-destructive analysis of biologic material with minimal sample preparation and reproducible success. Furthermore, Raman spectroscopy has already demonstrated clinical utility in a number of diseases, including analysis of tumor tissue in surgical oncology and neurosurgery, where it can allow for effective, in vivo determination of the tumor margins in real time, limiting the need for excessive resection of adjacent tissue.6, 7, 8

In the current study, Sugiyama and colleagues utilized Raman spectroscopy to identify novel spectral-based biomarkers of aneurysmal disease in vitro in Fbln5 and Fbln4 mouse models of TAA and in situ in explanted human aortic tissue. The authors were able to demonstrate clear differences between the spectral components of aortic tissue from either Fbln5 or Fbln4 mice and wild-type controls, as well as differences in ascending and descending aortic samples in the Fbln4 mutant mice. Further analysis led to identification of disease-specific collagen and elastic elements in the mouse models of aortic disease. These findings were supported by the examination of human aortic tissue samples where at least one elastic and collagen element was identified as elevated among aneurysmal samples when compared to healthy human control samples. This demonstrates the potential use of Raman spectroscopy for detailed molecular characterization of aortic tissue and potentially for clinical diagnostic use.

Aside from allowing detailed molecular analysis of in vivo and in situ tissues, as demonstrated in the current article, Raman spectroscopy has previously been demonstrated to allow for detailed studies of cell-state transitions with single-cell resolution. Hsu et al. were able to characterize biochemical profiles of different lineages from human-induced pluripotent stem cells and identify neural differentiation biomarkers using Raman spectroscopy to provide a better understanding of this transition as well as formulate a mechanism for quality control of neural stem cell selection for treatment applications. Using the targets identified in the current report, further investigation into the changes that aortic cells and the associated extracellular matrix proteins undergo during disease progression has the potential to create improved understanding of the dynamic cellular events involved in aneurysm pathogenesis.

Raman spectroscopy has also been used to study DNA methylation patterns in human cancer cells and murine stem cells. In their study, Daum et al. were able to utilize Raman spectroscopy to characterize high and low methylation states in different cell types, suggesting a mechanism of analysis and tracking of DNA conformation over time. Methylation changes can alter the cellular transcriptome in response to environmental stimuli, leading to large changes in global patterns of gene expression. The ability to study these changes in response to alterations in aortic hemodynamics and sheer stress that occur in healthy and aneurysmal aortas may lend additional insight into the pathogenesis of TAA and identify novel pathways that could be potential targets for therapeutic manipulation.

Finally, the authors identify possible in vivo clinical utility of Raman spectroscopy. Though there are diseases and procedures, such as cancer resection, where Raman spectroscopy already offers a clear benefit, the current risk of in vivo aortic analysis in humans appears to outweigh any possible benefit. However, as technology continues to evolve, allowing for improved, less invasive testing in all areas of medicine, it is conceivable to imagine these changes allowing for Raman spectroscopy to be a part of aortic surveillance for aneurysmal disease in the future, in particular if endovascular probes are developed that would allow for less-invasive analysis of the human aorta.