Myoglobinemia, Peripheral Arterial Disease, and Patient Mortality

• Type of Material: Article
• Authors: Ottis Scrivner, Emory University; Emma Fletcher, Baylor University; Carson Hoffmann, Emory University; Feifei Li, Emory University; Trevor Wilkinson, Baylor University; Dimitrios Miserlis, University of Texas Health Science Center San Antonio; Robert S Smith, Baylor Scott and White Medical Center; William T Bohannon, Baylor Scott and White Medical Center; Roy Sutliff, Emory University; William D Jordan, Emory University; Panagiotis Koutakis, Baylor University; Luke Brewster, Emory University
• Language: English
• Date: 2023-04-01
• Publisher: LIPPINCOTT WILLIAMS & WILKINS
• Publication Version: Final Published Version
• Copyright Statement: © 2023, Wolters Kluwer Health
• Final Published Version (URL): http://dx.doi.org/10.1097/XCS.0000000000000554
• Title of Journal or Parent Work: JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS
• Volume: 236
• Issue: 4
• Start Page: 588
• End Page: 598
• Grant/Funding Information: This work was supported by the NIH and US Dept of Veteran Affairs: R01HL143348; BX004707-01; RX003188-01; CX002366; Atlanta VA Medical Center (LB); RO1AG064420(S1) (PK).
• Keywords: GLOBIN; Surgery; PREVALENCE; Life Sciences & Biomedicine; Science & Technology; OUTCOMES; RISK-FACTORS; REDUCTASE

Abstract

BACKGROUND: Peripheral arterial disease (PAD) causes leg muscle damage due to inadequate perfusion and increases cardiovascular events and mortality 2- to 3-fold. It is unclear if PAD is a biomarker for high-risk cardiovascular disease or if skeletal muscle injury harms arterial health. The objective of this work is to test if serum myoglobin levels (myoglobinemia) are a marker of PAD, and if so, whether myoglobin impairs vascular health. STUDY DESIGN: Patient blood samples were collected from PAD and control (no PAD) patients and interrogated for myoglobin concentrations and nitric oxide bioavailability. Patient mortality over time was captured from the medical record. Myoglobin activity was tested on endothelial cells and arterial function. RESULTS: Myoglobin is a biomarker for symptomatic PAD and was inversely related to nitric oxide bioavailability; 200 ng/mL myoglobin in vitro increased endothelial cell permeability in vitro and decreased nitrate bioavailability. Ex vivo, 100 ng/mL myoglobin increased vascular tone in naive murine aortas approximately 1.5 times, impairing absolute vessel relaxation. In vivo, we demonstrated that myoglobinemia caused impaired flow-mediated dilation in a porcine model. Patients presenting with myoglobin levels of 100 ng/mL or greater had significantly more deaths than those with myoglobin levels of less than 100 ng/mL. CONCLUSIONS: Using a combination of patient data, in vitro, ex vivo, and in vivo testing, we found that myoglobin is a biomarker for symptomatic PAD and a potent regulator of arterial health that can increase vascular tone, increase vascular permeability, and cause endothelial dysfunction, all of which may contribute to the vulnerability of PAD patients to cardiovascular events and death.