Eur J Vasc Endovasc Surg 15, 7-17 (1998) REVIEW ARTICLE The Evidence for Exercise-induced Inflammation in Intermittent Claudication: Should we Encourage Patients to Stop Walking? P. V. Tisi and C. P. Shearman Department of Vascular Surgery, Southampton General Hospital, Southampton, U.K. Objectives: To review clinical and experimental evidence that exercise to the onset of calf pain in patients with intermittent claudication results in an inflammatory response, and to consider whether repeated inflammatory events induced by therapeutic exercise training may lead to progression of atherosclerosis. Methods: A literature search was performed to identify studies measuring biochemical markers of exercise-induced ischaemia-reperfusion injury in patients with intermittent claudication. Current theories of atherogenesis were reviewed and the use of acute-phase proteins as potential markers of vascular disease explored. Results: Exercise to the onset of calf pain results in an inflammatory response with free radical formation, neutrophil activation and systemic vascular endothelial damage. Acute-phase proteins such as C-reactive protein and serum amyloid A protein have exciting potential use as stable biochemical markers of disease in claudication. Conclusions: Further studies are needed to determine the effect of long-term exercise training on exercise-induced inflammation in claudication. Early work suggests, in fact, that exercise attenuates this inflammatory response. If this were confirmed then it would support the clinical impression that exercise training is beneficial in terms of symptomatic improvement and cardiovascular health in patients with intermittent claudication. Key words: Intermittent claudication; Ischaemia-reper)qlsion, Exercise, Acute-phase proteins. Introduction 30 years, although few of these studies have been well- designed randomised-controlled trials. 6-~° A recent The usual advice given to a patient with stable in- meta-analysis of 21 exercise training programmes termittent claudication is to "stop smoking and keep showed that training for at least 6 months by walking walking".~ In the general population, regular exercise to near-maximum pain tolerance produced significant can decrease the risk of future cardiovascular disease improvements in pain-free and maximum walking and improve health. 2'3 In view of this, increased phys- distances. 1~ Supervised exercise training has also been ical activity has been promoted as a strategy to improve shown to be more effective than percutaneous trans- the health of the nation. 4 For patients with intermittent luminal angioplasty in terms of walking distance up claudication, exercise undoubtedly has significant to 12 months following randomisation.12 However, benefit in terms of reduction of cardiovascular risk there was no significant difference between the two factors, optimised structural and metabolic per- treatment modalities at 6 years' follow-up. ~3 formance of skeletal muscle, improvement in rheo- In the face of this impressive evidence regarding logical parameters, development of collaterals, the efficacy of exercise training in claudication, why improved walking technique and marked psy- has exercise not been adopted universally as a first- chological benefit.5 Exercise training programs have line treatment? Although locally benign, intermittent been widely reported in the literature over the past claudication is associated with a 10-year mortality of at least 50%, predominantly from cardiovascular disease. 14 This corresponds to 3.8 times the relative risk of death compared to a control population. ~5 Evid- * Please address all correspondence to: Mr. P. V. Tisi, Department of Vascular Surgery, E-level, SouthamptonGeneral Hospital, Tremona ence is accumulating that exercise itself may be re- Road, SouthamptonSO16 6YD, U.K. sponsible for adverse inflammatory changes, which 1078-5884/98/010007+ 11 $12.00/0 © 1998 W.B. Saunders CompanyLtd. 8 P.V. Tisi and C. P. Shearman Claudication Calf pain (Ischaemia-reperfusion) (ischaemia) / ff S Neutrophil activation ~ ODFR ATP ", XD Proteases Eicosanoids Purine pathway \ , XO //~ Xanthine Increased vascular endothelial permeability Oxidation LDL Oxygen Hypoxanthine Rest (reperfusion) N~ Superoxide Mieroalbuminuria Atherogenesis Fig. 2. Generation of oxygen-derived free radicals during ischaemia- Fig. 1. Outline of ischaemia-reperfusion injury in intermittent clau- reperfusion in claudication. (ATP=adenosine triphosphate, XD= dication. (ODFR= oxygen-derived free radicals, LDL = low-density xanthine dehydrogenase, XO = xanthine oxidase). iipoprotein). SOD Catalase Superoxide H202 * H20 may be implicated in this excess cardiovascular mor- ,,. Fe 3+ tality. In 1924, Buerger perhaps recognised this prob- lem and suggested that walking for great distances Fenton Glutathione reaction peroxidase should be avoided in claudicants. 16 Instead, he pro- -increase intraeellular Ca 2+ -activates phospholipaseA2 Fe 2+ - _~ posed that passive exercises, such as alternate dis- -liberates arachidonic acid tension and emptying of the peripheral circulation by -eicosanoid synthesis leg elevation and dependency should be used to treat Hydroxyl claudication. Should we therefore encourage our patients to exercise to the onset of calf pain? This article l will explain the putative underlying mechanisms of -lipid peroxidation -oxidation of LDL exercise-induced inflammation in claudication and at- -macrophage activation tempt to rationalise the use of exercise as a treatment -? atherogenesis for intermittent claudication. Fig. 3. The role of oxygen radicals in vascular disease. (SOD= superoxide dismutase, H202=hydrogen peroxidase, LDL=low- density lipoprotein). to a fall in tissue adenosine triphosphate levels and accumulation of hypoxanthine (Fig. 2). Biochemical basis of ischaemia-reperfusion injury Physiologically, xanthine dehydrogenase (XD) in vascular endothelial cells converts hypoxanthine to The systemic effects of intermittent claudication may xanthine using nicotine adenine dinucleotide as a co- be subsequent to the phenomenon of ischaemia-re- factor. Hypoxia induces a calcium-induced protease perfusion injury (IRI). The underlying biochemical attack on XD forming xanthine oxidase (XO) - the "D- pathways are outlined in Fig. 1. IRI causes greater O conversion". 2° XO requires oxygen as a co-factor tissue damage from restoration of the blood supply which is provided on reperfusion, generating the following a period of ischaemia than from the original superoxide radical. Superoxide is also a product of ischaemic injury. 17'~s Claudicants experience repeated the "respiratory burst" of activated neutrophils via episodes of calf muscle pain on exercise (ischaemia) oxidation of nicotinamide adenine dinucleotide phos- followed by rest (reperfusion). Transient muscle isch- phate. 21 aemia is difficult to assess clinically. A reduction in Oxygen-derived free radicals (ODFR) are important transcutaneous oxygen tension (TcPO2) in skin over in the pathogenesis of vascular endothelial injury fol- the calf muscle following exercise may, however, reflect lowing ischaemia-reperfusion (Fig. 3). Superoxide in- underlying ischaemic changes. 19 During muscle isch- creases intracellular calcium concentration, which aemia, inadequate oxidative phosphorylation leads activates endothelial phospholipase A2. This liberates Eur J Vasc Endovasc Surg Vol 15, January 1998 Exercise-induced Inflammation in Intermittent Claudication 9 arachidonic acid from membrane phospholipids, is essential for neutrophil-mediated injury and re- which is the precursor for pro-inflammatory (thom- cruitment of further neutrophils to the site of in- boxane A2 and leukotriene B4) and anti-inflammatory flammation. (prostacyclin) eicosanoids. Thromboxane A2 (TXA2) Contrary experimental evidence has also suggested causes vasoconstriction, platelet aggregation, pro- that a circulating "neutrophil activator" is released motes neutrophil chemotaxis and increases vascular from ischaemic reperfused tissue, activating systemic permeability by disassembling actin microfilaments neutrophils which then plug the capillary network. In and widening interendothelial tight junctions. 22 Ac- support of this, Paterson used an ex vivo chemotactic tivated neutrophils are probably the main source of model, in which human reperfusion plasma obtained TXA2 in IRI. Leukotriene B~ (LTB4) is chemotactic for from aortic aneurysm surgery activated neutrophils in neutrophils and upregulates neutrophil-encothelial a rabbit dermabrasion lesion, resulting in increased adhesion in the post-capillary venule, leading to an microvascular permeability,as Interleukin-8 (IL-8), increase in microvascular permeability. Animal ex- which is synthesised by monocytes in response to perimental work using eicosanoid receptor antagonists interleukin-1 and tumour necrosis factor-a, has been has confirmed that these mediators are certainly im- suggested as the main neutrophil activator. 33 IL-8 acts portant in acute limb ischaemia23 and therefore may specifically on neutrophils promoting chemotaxis, perhaps have a role in claudication. neutrophil-endotheial adhesion, extravascular ac- In vivo, superoxide rapidly dismutates to hydrogen cumulation at the site of injury and release of ODFR peroxide, which may oxidatively damage protein. The and proteases. 3. highly reactive hydroxyl radical is released from hy- Current evidence suggests that IRI has important drogen peroxide in the Fenton reaction, catalysed by effects on endothelial nitric