Intraplaque Myeloperoxidase Activity as Biomarker of Unstable Atheroma and Adverse Clinical Outcomes in Human Atherosclerosis

James Nadel; Sergey Tumanov; Stephanie M Y Kong; Weiyu Chen; Nicola Giannotti; Vanathi Sivasubramaniam; Imran Rashid; Martin Ugander; Andrew Jabbour; Roland Stocker

doi:10.1016/j.jacadv.2023.100310

Intraplaque Myeloperoxidase Activity as Biomarker of Unstable Atheroma and Adverse Clinical Outcomes in Human Atherosclerosis

JACC Adv. 2023 Apr 26;2(3):100310. doi: 10.1016/j.jacadv.2023.100310. eCollection 2023 May.

Authors

James Nadel^{1

2

3}, Sergey Tumanov^{1

4}, Stephanie M Y Kong¹, Weiyu Chen¹, Nicola Giannotti⁵, Vanathi Sivasubramaniam², Imran Rashid^{6

7}, Martin Ugander^{8

9}, Andrew Jabbour^{2

3}, Roland Stocker^{1

10}

Affiliations

¹ Heart Research Institute, The University of Sydney, Sydney, Australia.
² Cardiology Department, St Vincent's Hospital, Sydney, Australia.
³ School of Medicine, University of New South Wales, Sydney, Australia.
⁴ Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.
⁵ Medical Imaging Science, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.
⁶ School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
⁷ Harrington Heart and Vascular Institute, University Hospitals, Cleveland, Ohio, USA.
⁸ Faculty of Medicine and Health, Kolling Institute, Royal North Shore Hospital, The University of Sydney, Sydney, Australia.
⁹ Department of Clinical Physiology, Karolinska University Hospital, and Karolinska Institutet, Stockholm, Sweden.
¹⁰ School of Life and Environmental Sciences, The University of Sydney, Sydney, Australia.

Abstract

Background: The detection of unstable atherosclerosis remains elusive. Intraplaque myeloperoxidase (MPO) activity causes plaque destabilization in preclinical models, holding promise for clinical translation as a novel imaging biomarker.

Objectives: The purpose of this study was to assess whether MPO activity is greater in unstable human plaques, how this relates to cardiovascular events and current/emerging non-invasive imaging techniques.

Methods: Thirty-one carotid endarterectomy specimens and 12 coronary trees were collected. MPO activity was determined in 88 individual samples through the conversion of hydroethidine to the MPO-specific adduct 2-chloroethidium and compared with macroscopic validation, histology, clinical outcomes, and computed tomography-derived high and low attenuation plaques and perivascular adipose tissue. Non-parametric statistical analysis utilizing Mann-Whitney U and Kruskal-Wallis tests for univariate and group comparisons were performed.

Results: Unstable compared with stable plaque had higher MPO activity (carotid endarterectomy: n = 26, 4.2 ± 3.1 vs 0.2 ± 0.3 nmol/mgp; P < 0.0001; coronary: n = 17, 0.6 ± 0.5 vs 0.001 ± 0.003 nmol/mgp; P = 0.0006). Asymptomatic, stroke-free patients had lower MPO activity compared to those with symptoms or ipsilateral stroke (n = 12, 3.7 ± 2.1 vs 0.1 ± 0.2 nmol/mgp; P = 0.002). Computed tomography-determined plaque attenuation did not differentiate MPO activity (n = 30, 0.1 ± 0.1 vs 0.2 ± 0.3 nmol/mgp; P = 0.23) and MPO activity was not found in perivascular adipose tissue.

Conclusions: MPO is active within unstable human plaques and correlates with symptomatic carotid disease and stroke, yet current imaging parameters do not identify plaques with active MPO. As intraplaque MPO activity can be imaged non-invasively through novel molecular imaging probes, ongoing investigations into its utility as a diagnostic tool for high-risk atherosclerosis is warranted.

Keywords: atherosclerosis; inflammation; myeloperoxidase; myocardial infarction; redox biology; stroke.