Supervised training improves endothelial function measured during induced ischemia in peripheral arterial disease.

Introduction: favorable effect of training on cardiovascular pathology is well documented in literature. Mechanisms evoked are the following: increased NO availability for reduction of oxidative stress, inflammation decrease, improvement of glucidic and lipidic metabolism, resetting of neuro-endocrine balance (1). These mechanism are also involved in the improvement of patients with peripheral arterial disease (PAD) treated with training. PAD is a model of inducible ischemia, in fact claudication is a condition in which ischemia/reperfusion phenomenon is present when walking is conducted till maximum pain (2). This phenomenon may produce a great amount of radical oxygen species with possible consequence on endothelium function. Xanthine oxidase is one of the most relevant enzyme involved in this process. Different types of training are proposed for PAD patients and there is not a consensus whether the ischemic pain should be reached during exercise. So we aimed to verify if maximal treadmill test (till pain) causes endothelial dysfunction, if oxidative stress is acutely aroused and if xanthine oxidase is involved. Therefore we aimed to verify if a training performed under the onset of ischemic pain can improve endothelial function ether at rest and after maximum tolerated exercise. Patients and methods: we enrolled 20 patients with PAD (16 males, 4 females, aged 65-77). Endothelium dependent dilation (EDD) was measured at humeral artery by ultrasound method, before and after maximal treadmill test (speed 3,2 km/h; slope 10%). We administered allopurinol 600 mg the day before and 600 mg 6 hours before a new treadmill test. Serum uric acid and lactate were determined throughout the study. Afterwards patients performed supervised training under pain onset for 20 days with physiotherapist overview. Every 7 days a new treadmill test was performed for updating training distance. At the end of the training period EDD was measured before and after a maximal treadmill test. Furthermore microcirculatory endothelium dependent dilation was measured at the skin of the forefoot by means of laser-Doppler (LD) after iontophoretic acetylcholine administration. Results: maximal treadmill test acutely reduced EDD (6,10,7 vs 9,20,9 %; p<0,05;). Allopurinol improved EDD (10,10,3 vs 9,40,6 %; p<0,05) with a reduced fall after maximal test (delta decrease -21,32,2 vs –33,21,2%; p<0,05). Training increased pain free walking distance (13112 vs 66,621 m; p<0,05) and absolute walking distance (27515 vs 125,840 m; p<0,05). EDD improved after training period (11,30,7 vs 9,20,9; p<0,05). The fall in EDD, observed during maximal treadmill test at the end of training period, was smaller than the one measured before training (delta decrease -15,52,4 vs –33,21,2%; p<0,005). Microcirculatory endothelium dependent dilation measured with LD increased after training (table). Table: microcirculatory flux with LD after iontophoretic acetylcholine. Acetylcholine 0,10 mA 10 s 20 s 40 s T 0 (% incr) 359 7015 12015 T 20 (%incr) 14738* 18222* 47054* (*p<0.005 T20 vs T0) Conclusions: we demonstrate that walking through maximal pain causes impairment of EDD, this is caused by oxidative stress and can be reduced by inhibition of xanthine oxidase. Aerobic training improves EDD and microcirculatory endothelial function, furthermore training reduces the drop of EDD during maximal exercise and increased oxidative stress. As a consequence these results suggest the training should be performed under the maximal pain. References 1. Brendle DC, Joseph LJ, Corretti MC, Gardner AW, Katzel LI. Effects of exercise rehabilitation on endothelial reactivity in older patients with peripheral arterial disease. Am J Cardiol 2001;87:324-9. 2. Andreozzi GM, Leone A, Laudani R, Deinite G, Martini R. Acute impairment of the endothelial function by maximal treadmill exercise in patients with intermittent claudication, and its improvement after supervised physical training. Int Angiol. 2007; 26:12-7.