Peripheral Artery Disease: The search for a biological marker

Identifier:  TDX:2568

Handle: https://hdl.handle.net/20.500.11797/TDX2568

Authors:  Hernández Aguilera, Anna

Abstract:
Peripheral artery disease (PAD) is a common manifestation of systemic atherosclerosis affecting peripheral arteries. Despite its high prevalence, PAD is often underdiagnosed because first stages of the disease are asymptomatic. The ankle-brachial index (ABI) is the most used test for PAD diagnosis although its limitations. There are additional circulating biomarkers of diagnosis not exclusively for PAD but for atherosclerosis in general. Inflammation, oxidation, vascular remodeling and mitochondrial dysfunction play an important role in the development of atherosclerosis. We hypothesized that an increased knowledge on these processes may provide circulating biomarkers for the disease as well as possible therapeutic strategies. In Study 1, we investigated the immunohistochemical expression of paraoxonases (PON) and chemokines in arteries of PAD patients. Results showed that PON1, PON3, chemokine (C-C motif) ligand 2 (CCL2) and atypical chemokine receptors (ACKR) DARC and D6 were increased in atherosclerotic arteries, suggesting that both paraoxonases and chemokines play a key role in the development of atherosclerosis. Extracellular matrix (ECM) turnover is also involved in vascular remodeling. In Study 2, by combining histological and proteomics approaches, we observed that atherosclerotic arteries had a specific protein profile in which ECM-related components were underexpressed, suggesting a possible degradation of the ECM. Among a measured a panel of neo-epitopes, Versican and type IV collagen degradation fragments showed potential as biomarkers to segregate patients across the spectrum of PAD. Impaired metabolism and mitochondrial dysfunction may also predispose to disease. In Study 3, we used a targeted metabolomics methodology to assess the plasma metabolome of PAD patients. Many of measured metabolites were connected not with PAD, but with associated comorbidities, age or body mass index. Among remaining metabolites, (Iso)citrate and glutamate were useful for PAD diagnosis and also for an early detection of the disease.