Abstract
Exercise is important for maintaining health, and for the prevention and treatment of many cardiovascular diseases. Unfortunately, some individuals face significant barriers to exercise. Patients with peripheral arterial disease (PAD) are limited by debilitating muscle pain when walking as a result of poor blood supply. In PAD this exercise intolerance can exacerbate disability, comorbidities and mortality.
The aim of this thesis was to investigate forms of stress that are components of exercise or which mimic its effects, so that an affected individual can access the benefits when exercise is impractical. Two novel stressors were investigated: ischaemia and heat. Ischaemia, the restriction of blood supply, was assessed as a short-term cardioprotective strategy in a randomised controlled trial of 85 patients undergoing major vascular surgery. Surgery involves elevated cardiovascular risk and anticipated ischaemia- reperfusion injury. Ischaemia administered as remote ischaemic preconditioning (RIPC) has been shown to limit myocardial injury in animal studies and in some clinical populations. Here, RIPC was employed as an alternative to exercise in PAD patients undergoing vascular surgery. RIPC comprised 3 x 5-min cycles of upper-limb ischaemia 24 h before and immediately before surgery, compared with sham occlusions. No cardioprotective effect of RIPC was evident, based on the difference in frequency and magnitude of injury between groups. Of note was a high incidence of myocardial injury in both groups, as well as several difficulties associated with diagnosing injury from infarction in this setting.
Driven by the negative trial results and the need for a RIPC biomarker to facilitate optimisation and understanding of RIPC, a further mechanistic study was performed in healthy, young controls (n = 10). Circulatory microRNAs were explored as potential biomarkers of the induction of RIPC. A likely biomarker candidate was not found in the circulatory microRNAs.
The second stressor was heat, a product of exercise, which enhances many of the cardiovascular effects of exercise. Heat was examined acutely, for its potential to mediate chronic benefit for those living with PAD. Heat was applied via lower-limb hot- water immersion (30 min at 42 °C). Hot-water immersion was assessed first in healthy, young volunteers (n = 10) to characterise the nature and the magnitude of the responses. Next, the same intervention was employed in PAD patients (n = 11) and healthy, elderly controls (n = 10). In all groups, acute heat stress induced appreciable thermal (core temperature increase), systemic (heart rate increase and blood pressure decrease) and haemodynamic (lower-limb perfusion and shear rate increases) responses. Further studies are needed to determine whether these acute benefits translate into improved vascular health.
The goal of the thesis was to evaluate novel stress conditioning approaches for PAD patients – in the short-term to provide protection during surgery, and in the long-term as conditioning vascular health and functional capacity. Although RIPC did not induce cardioprotection, heat demonstrated therapeutic potential to acutely induce favourable strain. Heat, when repeated, may offer a powerful tool for cardiovascular conditioning in patients with PAD, and others who face barriers to traditional exercise.