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