Introduction: Previous studies have suggested a beneficial effect of limb ischaemia in reducing myocardial infarct size in animal models. Human studies of remote ischaemia have focussed on the demonstration of the reduction of biomarkers of myocardial injury following both cardiac and non-cardiac surgery. However, there have been no studies investigating the physiological effects of limb ischaemia upon patients with stable coronary disease. The phenomenon of warm-up angina provides a useful model to explore this question. Warm-up angina describes the improvement in exercise observed during a second effort after a brief period of rest following an initial effort. The purpose of our investigation was twofold: (1) to determine if limb ischaemia could reproduce the benefits of the first effort in a warm-up angina model; (2) to determine if the beneficial effect of first exercise and limb ischaemia (if any) could be modified by the free radical scavenger N-acetylcysteine (NAC), suggesting a shared mechanism of cardioprotection.
Methods: Having withdrawn gradually from anti-anginal therapy, 30 patients with stable coronary disease were randomly assigned to each of four different combinations of NAC and limb ischaemia on four separate days in a single blind cross-over design: (A) no NAC, no limb ischaemia; (B) no NAC, limb ischaemia; (C) NAC, no limb ischaemia; (D) both NAC and limb ischaemia. Limb ischaemia was produced by three 5-minute cycles of blood pressure cuff inflation to 200 mm Hg around the arm alternating with 5 minutes of reperfusion just before the first treadmill test on any particular day. NAC was administered as an oral preparation for 48 h before exercising. On each day three sequential treadmill tests (ETT 1, 2 and 3) were performed using a standard Bruce protocol, with 15 minutes separating the first and second exercise to provoke a warm-up effect, and 90 minutes between the second and third exercise to account for a training effect. Primary endpoints were the time to 1 mm ST depression, the rate pressure product (RPP) at 1 mm ST depression and the RPP at peak equivalent workloads.
Results: Time to 1 mm ST depression between ETT1 and ETT2 increased significantly in the untreated (p = 0.0097) and limb ischaemia (p = 0.012) groups, but this effect was abrogated by NAC. The degree of ST depression at peak equivalent workloads was significantly lower in groups A and B, and once again this benefit appeared to be removed by NAC. However, the RPP at 1 mm ST depression was significantly lower in group B compared with group A. The RPP at peak equivalent effort was significantly higher in group A compared with the other groups (p<0.01), an effect primarily driven by a higher heart rate in group A.
Conclusions: Both limb ischaemia and NAC appear to increase the time taken to develop ischaemia. NAC abrogates the warm-up effect as measured by ST shift, but not RPP, suggesting a separate mechanism to these responses to ischaemia.