The effect of revascularization on recovery of mitochondrial respiration in peripheral artery disease: a case control study

Abstract

Background Peripheral arterial disease (PAD) is accompanied by myopathy characterized by mitochondrial dysfunction. The aim of this experimental study was to investigate the effect of revascularization procedures on mitochondrial function in ischemic and non-ischemic muscle. Methods Muscle biopsies from patients with symptomatic stage IIB/III PAD caused by isolated pathologies of the superficial femoral artery were obtained from muscle regions within the chronic ischemic muscle (gastrocnemius) and from non-ischemic muscle (vastus lateralis) before and 6 weeks after invasive revascularization. High-resolution respirometry was used to investigate mitochondrial function and results were normalized to citrate synthase activity (CSA). Results are given in absolute values and fold over basal (FOB). Results Respiratory states (OXPHOS (P) and electron transfer (E) capacity) normalized to CSA decreased while CSA was increased in chronic ischemic muscle after revascularization. There were no changes in in non-ischemic muscle. The FOB of chronic ischemic muscle was significantly higher for CSA (chronic ischemic 1.37 (IQR 1.10–1.64) vs. non-ischemic 0.93 (IQR 0.69–1.16) p = 0.020) and significantly lower for respiratory states normalized to CSA when compared to the non-ischemic muscle (P per CSA chronic ischemic 0.64 (IQR 0.46–0.82) vs non-ischemic 1.16 (IQR 0.77–1.54) p = 0.011; E per CSA chronic ischemic 0.61 (IQR 0.47–0.76) vs. non-ischemic 1.02 (IQR 0.64–1.40) p = 0.010). Conclusions Regeneration of mitochondrial content and function following revascularization procedures only occur in muscle regions affected by malperfusion. This indicates that the restoration of blood and oxygen supply are important mediators aiding mitochondrial recovery.

The Role of Mitochondrial Function in Peripheral Arterial Disease: Insights from Translational Studies

“…Differences were restricted to ischemic muscle regions, while non-ischemic muscle regions did not show any changes in the measured parameters. In this cohort, we were able to demonstrate that the effect of the restoration of blood supply has a greater impact on mitochondrial recovery than an increase of physical activity levels [59]. The exact mechanisms and the contributory role of ROS within the recovery of mitochondria after revascularization procedures need to be investigated in upcoming trials.…”

“…This led us to the conclusion that mitochondrial plasticity allows for mitochondrial recovery, at least in mild forms of PAD [58]. As we solely included patients with flow-limiting pathologies of the superficial artery, we defined ischemic (gastrocnemius muscle) and non-ischemic (vastus lateralis muscle) muscle regions [59]. Differences were restricted to ischemic muscle regions, while non-ischemic muscle regions did not show any changes in the measured parameters.…”

Effect of Revascularization on Intramuscular Vascular Endothelial Growth Factor Levels in Peripheral Arterial Disease

“…The pathologic elevation of VEGF levels in pretherapeutic PAD could be part of a physiological compensatory mechanism to overcome the resulting peripheral hypoxia [ 19 ]. An upregulation to compensate for hypoxia in PAD as a multisystem disease was also found in mitochondrial respiratory chain abnormalities [ 15 ]. However, the formation of new blood vessels also constitutes a hallmark of cancer and sustains tumor growth.…”

“…Perfusion of the vastus muscle was provided by deep femoral and lateral circumflex femoral arteries, which were proven to be patent in our patients. The technique of muscle sampling using a Bergstrom needle has been described by Gratl et al [ 15 ]. Furthermore, they provided evidence that the gastrocnemius muscle can in fact be regarded as ischemic, whereas the vastus muscle can be considered healthy in comparison to healthy controls [ 15 ].…”

“…The technique of muscle sampling using a Bergstrom needle has been described by Gratl et al [ 15 ]. Furthermore, they provided evidence that the gastrocnemius muscle can in fact be regarded as ischemic, whereas the vastus muscle can be considered healthy in comparison to healthy controls [ 15 ].…”