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In patients with CLI, pathophysiological abnormalities at a number of levels of the vascular tree combine to produce the symptoms and clinical sequalae of the condition [21]. These are summarized in Fig.?2 and include both macro- and microcirculatory defects that result in maldistribution of the skin circulation in addition to the overall decreased perfusion resulting from arterial stenosis. The microcirculatory http://www.selleck.cn/products/Bortezomib.html abnormalities provide possible targets for drug intervention to manipulate and improve microcirculation to either augment macro revascularization or provide treatment for patients who are unsuitable for such procedures. The overall aims of management in patients with CLI are to relieve ischaemic pain, heal ulcers, prevent limb loss, improve function and quality of life and prolong survival. A number of medical interventions have been proposed and/or investigated. The evidence for or against the use of these is summarized in Table?2 and is explored in more detail below. As discussed previously, individuals with CLI are known to be at high risk of cardiovascular disease. Therefore, they constitute a population http://www.selleckchem.com/products/Everolimus(RAD001).html that needs aggressive risk factor management. The Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II) [18-20], American College of Cardiology/American Heart Association ([1, 22], European Society of Cardiology [23] and Scottish Intercollegiate Guidelines Network [24] have all published comprehensive guidelines for management of patients with PAD. Although treatment of the risk factors outlined below has not been studied exclusively in patients with CLI, evidence from patients with PAD has been extrapolated to include this subgroup. The association between smoking and increased risk of atherosclerosis has been recognized for a long time. Indeed, mortality, risk of amputation, http://www.selleckchem.com/products/PD-0332991.html peripheral graft occlusion and cardiovascular event rate are all dose-dependently correlated with tobacco smoking [25-27]. A systematic review of 20 studies showed that quitting smoking was associated with a 36% relative risk reduction in mortality compared with continuing to smoke [risk ratio (RR) 0.64, 95% confidence interval (CI) 0.58�C0.71] [25]. The impact of smoking cessation on limb viability is less clear; therefore, the importance of cessation should be presented to patients as a way of reducing the risks of cardiovascular events, disease progression and amputation, rather than as a symptomatic treatment. There is a large evidence base of measures to increase smoking cessation [28-31]. Elevated levels of total cholesterol, low density lipoprotein (LDL) cholesterol, triglycerides and lipoprotein (a) are independent risk factors for PAD, whereas elevated high density lipoprotein (HDL) cholesterol and apolipoprotein (a-1) levels are protective. The TASC II guidelines [18-20] recommend that LDL cholesterol should be lowered to