Myoglobinemia, Peripheral Arterial Disease, and Patient Mortality

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.

Photodynamic Therapy for Atherosclerosis

“…Additionally, myoglobin may be involved in the recruitment and activation of immune cells, such as macrophages, which play a role in the inflammatory response associated with atherosclerosis. The exact mechanisms by which myoglobin influences atherosclerosis are not fully understood, and research in this area is ongoing [64][65][66]. Troponin T (Figure 4) is a protein primarily known for its role in muscle contraction, particularly in cardiac muscle.…”

Oxidative damage in the gastrocnemius predicts long-term survival in patients with peripheral artery disease

“…At the biochemical level the myopathy is characterized by oxidative damage, mitochondrial dysfunction, cytoskeletal disintegration and upregulation of cytokines [15][16][17][18]20,21,25,26,[29][30][31][32][33][34][35][36][37] . Work from several laboratories including our own has demonstrated that this myopathy is closely related to leg function, daily activity, quality of life and mortality of PAD patients [38][39][40][41][42][43][44][45][46] . In regards to mortality, our group recently demonstrated 47 that two basic biochemical biomarkers of PAD myopathy, protein concentration and mitochondrial content in gastrocnemius biopsies, are predictors of 5-year mortality in PAD patients.…”