Oxidative stress-related factors in abdominal aortic aneurysm: potential clinical implications - PhDData

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Oxidative stress-related factors in abdominal aortic aneurysm: potential clinical implications

The thesis was published by Vats, Sakshi, in January 2023, Lund University.

Abstract:

Abdominal aortic aneurysm (AAA) is a mostly silent vascular disease, with a rupture-related mortality rate exceeding 80%. To aid in future diagnosis and prognosis efforts, the studies included in the present thesis have explored the role of specific oxidative stress-related factors in the context of AAA using two population-based cohorts: AAA screening cohort of 65-year-old males (n = 421) and the Malmö diet and cancer study (MDCS) (n = 25252). In Paper I, global DNA methylation (enzyme-linked immunosorbent assay (ELISA)) and homocysteine (diagnostic enzymatic assay) levels were investigated in the AAA screening cohort. Increased global DNA methylation and homocysteine levels were observed in AAA, with positive linear associations with baseline aortic diameter. However, no significant association was found with AAA growth, suggesting different mechanisms in initiation and progression. Paper II characterizes a novel mitochondrial genetic landscape in AAA from 48 cases and 48 matched controls from the AAA screening cohort. Whole mitochondrial genome sequencing revealed differential mutational landscapes in AAA as compared to the non-AAA group. MtDNA mutational load was significantly elevated in AAA, particularly in the regulatory and conserved region (MT-TAS2). Lower mitochondrial copy number exacerbated the effect of mtDNA mutation in AAA. A novel 24 bp mtDNA duplication was found exclusive to AAA cases, and the northern-European JTU mitochondrial haplogroup was associated with family history of AAA. Paper III explores genetic variations in oxidative stress-related genes and antioxidant vitamin intake in incident intact AAA and ruptured AAA (rAAA) in the MDCS cohort. A variant in NOX3 gene was associated with higher rAAA risk, while antioxidant vitamins, riboflavin, and folate reduced intact AAA incidence. Both the studied genetic background and sex significantly modified the effect of specific vitamins’ intake on intact AAA risk ,overall, suggesting a complex gene-sex-vitamin interplay in AAA. Paper IV investigates hemoglobin (Hb)/heme and their scavengers in the AAA screening cohort using colorimetric assays including ELISAs, droplet digital PCR (ddPCR), and allelic discrimination assay. Elevated plasma heme levels and reduced heme oxygenase-1 (HO-1) levels were associated with AAA, independent of potential confounders. The addition of heme to a previous diagnostic model improved it significantly. Whole blood Hb and plasma hemopexin (Hpx) levels were associated with AAA growth rate. Overall these findings indicate the disruption of heme homeostasis in AAA. These collective findings from the thesis underscore the multifaceted nature of oxidative stress-related factors in AAA pathogenesis, emphasizing their potential roles in diagnosis, prognosis, and potential therapeutic interventions. Future research endeavors are encouraged to continue investigating these complex factors and their interplay for reliable clinical translation.



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