The effect of different forms of exercise on the clinical, systemic and local biological responses in intermittent claudication

Author: Christopher Delaney

Delaney, Christopher, 2015 The effect of different forms of exercise on the clinical, systemic and local biological responses in intermittent claudication, Flinders University, School of Medicine

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Consensus guidelines recommend that supervised exercise training (SET) should be made available as a treatment for adults with intermittent claudication (IC) on the basis of high quality evidence demonstrating improvement in walking performance following SET of sufficient intensity to induce claudication pain. Although treadmill-based SET is currently recommended, the optimal form of exercise is unknown and the impact of SET on the systemic and local biological responses of patients with IC has not previously been assessed. The study presented in this thesis sought to determine, in adults with IC, whether 12 weeks of SET combining the additive effect of supervised interval based treadmill training with lower limb resistance exercises would facilitate a greater clinically meaningful response in the primary outcome of pain free walking distance (PFWD) compared with supervised treadmill based training alone. The study also assessed whether the potential of supervised interval based treadmill training with lower limb resistance exercise training to limit exposure to ischaemia reperfusion injury, would result in a more positive effect on secondary outcomes and markers of long term cardiovascular health compared with the recommended treadmill based training regimen. These outcomes and markers included endothelial function, quality of life (QoL), body composition and systemic inflammatory burden. The 6-minute walk test (6MWT) was used to assess PFWD. Markers of endothelial function were measured, including flow mediated dilatation, reactive-hyperemia peripheral arterial tonometry, serum nitric oxide (NO) and asymmetric dimethyl arginine (ADMA). Body composition was assessed using dual energy x-ray absorptiometry and proteomic analysis of the proteolytic calpain system was undertaken. Dietary intake and QoL were recorded using food frequency questionnaires and the Australasian Vascular QoL Index respectively and an array of inflammatory cytokines were assayed using enzyme-linked immunosorbent assay. While neither exercise regimen was superior with respect to the primary outcome of PFWD, QoL improved in both groups. The treadmill-based SET resulted in a worsening of the biological marker of endothelial function (NO) and a relative loss of skeletal muscle mass which may be attributable to the increased level of activity of the proteolytic calpain enzyme. A combination based SET facilitated beneficial physiological effects including a gain in skeletal muscle mass, a relative reduction in calpain activity and a reduction in levels of the NO inhibitor ADMA. The systemic inflammatory response to exercise in both groups was difficult to interpret, but raised the possibility that SET in patients with IC may induce a pro-inflammatory response, an adaptive anti-inflammatory response or an immunosuppressive response. The study presented in this thesis demonstrates that treadmill-based exercise as a treatment for IC may be detrimental and challenge whether treadmill-based exercise training should remain the recommended treatment for patients with IC. The lack of significant improvement observed in walking performance means that the combination based SET cannot be recommended as a suitable alternative to a treadmill-based SET, however, with appropriate modifications, a combination based SET may have a role to play in the future. Further large scale work is required to address the clinical need to look at better ways to design exercise programs for maximal benefit rather than harm. Consideration should also be given to long follow-up periods to facilitate the assessment of cardiovascular outcomes to ultimately determine whether or not the changes observed in the study presented in this thesis truly do manifest as detrimental to long-term health outcomes.

Keywords: Peripheral arterial disease, intermittent claudication, supervised exercise training, endothelial function, inflammation, ischaemia-reperfusion injury, diet, nutrition, calpains
Subject: Medicine thesis

Thesis type: Doctor of Philosophy
Completed: 2015
School: School of Medicine
Supervisor: Prof Ian Spark