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