Pyruvate and lactate as local prognostic biomarkers of patient outcome after achilles tendon rupture

Abstract

Background Acute Achilles tendon rupture (ATR) is a frequently disabling injury, which exhibits unclear variability in long‐term functional and patient‐reported outcomes. Biomarkers from early healing, which have been shown to be prognostic of long‐term outcome would facilitate the development of improved treatment methods. Hypothesis/Purpose The aim of this study was to assess essential metabolites pyruvate and its product lactate, as early biomarkers in relation to long‐term functional‐ and patient‐reported outcome after ATR. Study design Prospective cohort study. Methods A total of 124 patients (103 men, 21 women; mean age 40 ± 7 years) with ATR, treated with uniform anesthetic and surgical technique, were prospectively assessed. At two weeks post‐injury pyruvate and lactate concentrations were assessed in both the injured and uninjured limbs using microdialysis followed by enzymatic quantification. The ratios of the concentration in the injured versus uninjured limb of pyruvate (pyruvate‐r) and lactate (lactate‐r) were calculated as well as the lactate/pyruvate ratios (L/P‐r). At 12 months, patient‐reported outcome was examined using self‐reported questionnaires; Achilles tendon Total Rupture Score (ATRS), Foot and Ankle Outcome Score (FAOS), and physical activity score. At 12 months, functional outcome was studied using the validated heel‐rise test. Results Elevated pyruvate‐r, at two weeks, was significantly associated with total ATRS (R = 0.254, P = 0.028), less loss in physical activity (R = 0.241, P = 0.039), less experience of pain in FAOS (R = 0.275, P = 0.032), and a higher number of heel‐rise repetitions on injured side (R = 0.230, P = 0.040) at 12 months. Increased lactate‐r was related with less strength limitations in the calf (R = 0.283, P = 0.011), while the elevated lactate‐pyruvate ratio, notably, was related to more limitations in walking on uneven surface (R = −0,243, P = 0.027). The findings were verified by multiple linear regression taking confounding factors into consideration. Conclusion This study established that the metabolite pyruvate is a good potential biomarker, prognostic of patient outcome at the one‐year follow‐up after ATR surgery. These novel findings suggest that local biomarkers could be developed at an early‐stage screen for new ATR treatments.

Nonoperative or Surgical Treatment of Acute Achilles’ Tendon Rupture

“…Intermittent pneumatic compression (IPC) reduces the risk of DVT and improves healing of the tendon by in the production of lactate or ethanol. High pyruvate levels at the tendon rupture site and an increased pyruvate/lactate ratio are favorable prognostic factors for tendon healing, long-term patient-reported outcomes, and functional outcomes196 . This correlation may be a key factor in understanding tendon healing and improving treatment methods through future research197 .…”

Tendon and multiomics: advantages, advances, and opportunities

“…A wide variety of small metabolites are of potential interest relating to pain, mechanisms of injury, and repair in tendon. Addevico et al 74 showed that during recovery after surgical treatment of Achilles tendon rupture, there was a positive correlation between pyruvate concentrations 2-months after surgery and a positive general outcome after one year. Pyruvate increases the expression of antioxidants that act as an anti-fibrotic agent, minimize collagen type III, and reduce oxidative stress on collagen fibrils, therefore reducing fibrosis and inflammation.…”

Higher pyruvate levels after Achilles tendon rupture surgery could be used as a prognostic biomarker of an improved patient outcome

“…The conception that pyruvate exerts crucial actions in tendon healing is supported by a recent study [2]. During wound healing, pyruvate has been shown to display anti‐fibrotic and antioxidant actions, which reduce the fibrotic collagen type III in favour of the mature and strong collagen type I [10, 22, 31].…”

“…The observation that improved patient outcome is associated with higher concentrations of pyruvate, is supported by studies demonstrating the underlying mechanisms of action of pyruvate in tendon healing and indicative of a potential tendon regenerative effect of pyruvate supplementation. The idea of adding pyruvate to the healing tendon to promote the regenerative repair process, is appealing and substantiated by other studies, but necessitates verification from prospective studies [2, 16, 31].…”

“…Pyruvate supplementation during wound healing accelerated migration of fibroblasts and myoblasts to promote wound gap closure [16]. Earlier studies have demonstrated that it is possible to assess the concentrations of lactate and pyruvate in human ATR healing using microdialysis [9] and that the ratio of lactate and pyruvate in human ATR healing is related to patient outcome [2]. The ratio of lactate/pyruvate, which is an indirect measure of the concentration of tissue hypoxia, is being used as a clinical marker for patient outcome after traumatic brain injury [11, 19, 22, 23].…”