Effects of Fish Oil Supplementation on Protease Levels in the Microenvironment of Chronic Venous Leg Ulcers: A Randomized Clinical Trial

Abstract

In the U.S. alone, the average annual incidence of chronic venous leg ulcers (CVLUs) in individuals aged 65+ is 2.2% with payer burden reaching ~$35 billion. Moreover, the incidence is expected to rise dramatically because CVLUs are associated with aging and obesity. CVLUs are difficult to treat, frequently recur, and lead to a reduced quality of life. Therefore, adjuvant therapies to standard care are needed to help improve healing outcomes. High levels of neutrophil-derived proteases in CVLU microenvironments are associated with slow healing. The bioactive components of fish oil, eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA], have been shown to reduce neutrophil activity in animal models of wounds, but have not been tested in humans with CVLUs. The purpose of this secondary analysis of data derived from a randomized, controlled study conducted at The Ohio State University Clinical Research Center was to determine the effects of EPA+DHA therapy on 1) levels of neutrophil-derived proteases in the fluid of venous leg ulcers, and 2) wound healing over an 8-week interval in patients with CVLUs. For 8 weeks, EPA+DHA Group participants (n=16) consumed an EPA+DHA supplement and Control Group participants (n=19) consumed a placebo. Plasma samples were evaluated at 0, 4 and 8 weeks to quantify EPA+DHA levels. Wound fluid was collected at the same time points to quantify neutrophil-derived proteases: matrix metalloproteinase-8 (MMP-8) and human neutrophil elastase (HNE). Sociodemographic and body mass index (BMI) data were also collected. Descriptive statistics, t-tests and Spearman’s Rho were used to analyze data. On average, the age of the total group was 60.6 years (SD = 12.0) and BMI was 41.7 (SD = 11.5). The majority were male (60%), Caucasian (74%), and lived alone (51%). No significant differences in age or BMI emerged between groups. Plasma levels of EPA+DHA increased significantly in the EPA+DHA group at 4 weeks and at 8 weeks compared to baseline (p=0.05). There were no significant differences in protease levels within or between groups at any time point, however there was a downward trend in levels of MMP-8 over time in the EPA+DHA Group and a significant negative relationship emerged between MMP-8 and healing at Week 8 (p = 0.04). In summary, the data indicate that higher levels of some neutrophil-derived proteases are associated with slower CVLU healing and suggest that EPA+DHA therapy may be helpful in reducing levels of some neutrophil-derived proteases in the microenvironment associated with slower healing. High BMIs suggest that interventions to help CVLU patients reduce weight may decrease risk for chronic diseases such as diabetes and cardiovascular disease that are also associated with healing complications. Additional studies are needed to test higher EPA+DHA doses for longer intervals in larger, more diverse samples of CVLU patients.