Inflammatory Mediators Across the Spectrum of Ankle-Brachial Index

Abstract

Aim: Peripheral artery disease (PAD) is a manifestation of atherosclerosis with poor prognosis. It is generally complicated by vascular calcification, which is located either in the intima as patchy infiltrates; or circumferentially in the media, also known as medial arterial calcification (MAC). Obstructive PAD is reflected by low anklebrachial index (ABI ≤ 0.9), whereas MAC is revealed by high ABI (ABI > 1.4). Considering the increase in cardiovascular mortality at both ends of the ABI spectrum, this study aimed to explore the underlying pathology through cytokines with established prognostic significance; namely pentraxin-3(PTX3), high sensitivity C-reactive protein (hsCRP), copeptin, soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), NT-proBNP, and neopterin. Methods: We categorized 180 patients with previous multivessel coronary artery bypass grafting surgery into three groups based on their ABI measurements; 60 patients with ABI ≤ 0.9, 60 patients with ABI within 0.91 and 1.4 (normal ABI), and 60 patients with ABI > 1.4 constituted the “PAD,” “normal,” “MAC” groups, respectively. The circulating levels of the biochemical markers were determined. Results: In the PAD group, the cytokine levels with predominantly proatherogenic actions such as PTX3, hsCRP, copeptin, and sTREM-1 were increased and these cytokine levels declined as the ABI increased. In the MAC group, the cytokine concentrations with pleiotropic actions such as NT-proBNP and neopterin increased and; NT-proBNP and neopterin concentrations decreased as ABI decreased. The linear regression analysis revealed that neopterin ( β = 0.72), PTX3 ( β = −0.32), and copeptin ( β = −0.48) were independent predictors of ABI. Conclusions: These findings suggest that different inflammatory pathways influence the pathology at the opposing ends of the ABI spectrum. Consequently, we suggest that PTX3, copeptin, and neopterin are promising biomarkers for future research.

Assessment of Serum Neopterin as a Biomarker in Peripheral Artery Disease

“…According to Avanzas et al [14], elevated serum NTP predicts future adverse cardiac events in patients with chronic stable angina pectoris. Furthermore, some studies demonstrated an association of NPT with the ankle-brachial index (ABI) and increased mortality of patients with vascular calcification or patients undergoing angiography [10,15,16]. Contrastingly, Shirai et al [6] reported that NPT level increased in coronary lesions and circulating blood in patients with CAD to counter inflammation and atherosclerosis.…”

Ankle-Brachial Index is a Predictor of Future Incident Chronic Kidney Disease in a General Japanese Population

“…Various other mechanisms associated with an abnormal ABI may contribute to CKD, further supporting our findings. Ozkaramanli Gur et al reported increased cytokine levels in both low and high ABI groups in patients with previous coronary artery bypass grafting 41) . Therefore, both low and high ABI groups may have vascular damage in the kidney via circulatory cytokines.…”

Copeptin, B-type natriuretic peptide and cystatin C are associated with incident symptomatic PAD

“…Studies on plasma biomarkers and incident PAD are few. One longitudinal study links cystatin C and incident PAD (Yang et al 2017), whereas only cross-sectional studies show relations between N-BNP (Falkensammer et al 2015), copeptin (Ozkaramanli et al 2018), and PAD in patients with prevalent cardiovascular disease. In a cross-sectional study comparing male patients with IC to an age-and diabetes matched control group (Kollerits et al 2013), both MR-proADM and MR-proANP were associated with PAD.…”

“…Copeptin acts as a non-specific marker of acute illness and disease severity, and plasma concentrations are elevated in acute cardiac conditions, such as myocardial infarction (Mueller et al 2018). As elevated levels of copeptin are cross-sectionally associated with ankle-brachial index in a population with advanced coronary artery disease (Ozkaramanli et al 2018), suggesting a relationship with PAD, it was relevant to prospectively relate levels of this marker to incident clinically relevant PAD.…”