Potential relationships between inflammatory markers and invasive treatment of PAD and CLI have also been evaluated (Table 13.1). Different markers such as high sensitivity (hs)-CRP, fibrinogen, and serum amyloid A (SAA) measured preoperatively in patients planned for lower extremity bypass all correlate with an increased risk for later adverse graft-related or cardiovascular events [43]. For hs-CRP, this relationship persisted even in multivariable analysis. In the post-treatment period after both open and endovascular repair in different vascular segments, several of the above-mentioned platelet and leukocyte mechanisms are further activated. Such post-interventional patterns have also mainly been investigated after interventions in coronary vessels, however. For example, levels of P-selectin [44] mediating platelet-leukocyte binding [45] are increased, and leukocyte-platelet interactions are increased after percutaneous coronary interventions [46]. In coronary blood, both expression of the activated platelet fibrinogen receptor [47] and release of chemoattractants affecting neutrophils [48] increase after endovascular coronary interventions. Reports on patterns of inflammatory substances during and after invasive vascular interventions for PAD are scarcer. In an observational study with repeated arterial sampling from 14 patients undergoing angiography for aortoiliac atherosclerotic disease, 9 of whom underwent PTA, we could not demonstrate any definite signs of leukocyte activation during or immediately after peripheral angiography [49]. The levels of inflammatory mediators after peripheral vascular interventions are not clinically irrelevant, however, and the occurrence of restenosis after vascular injury, such as for example an episode of invasive treatment, also has inflammatory features. A postischemic macrophage activation state evaluated in an animal model has been suggested as a new potential therapeutic approach to protect tissues from necrosis and promote tissue repair during CLI [50]. As no definite relationships have been reported between levels of inflammatory mediators and the efficacy of interventions, inflammatory mediators cannot yet be used to determine the best treatment of a certain patient.

Even if the prognostic importance of inflammatory activation is less well established in PAD and CLI than in patients with coronary or precerebral atherosclerosis, some observations about the relevance of inflammatory activation for prognosis have been presented also in PAD patients (Table 13.1). Elevated levels of inflammatory mediators seem to be indicators of a more severe prognosis concerning both local progression of atherosclerosis in the affected limb and acute events occurring in other vascular territories. The first mechanism is exemplified by the fact that both CRP and IL-6 levels predict local progression of atherosclerosis in the lower limb during 12 year follow-up of the ankle-brachial index (ABI) [51].

A recent investigation showed that patients with CLI show significantly higher α-defensin and hs-CRP levels compared with patients with intermittent claudication (IC) [52]. Furthermore, within the IC group high concentrations of α-defensin and high hs-CRP conferred a five times higher risk for cardiovascular mortality during follow-up than in patients with either high α-defensin or high hs-CRP. The addition of α-defensin or hs-CRP to conventional risk factors thus improved risk prediction concerning cardiovascular mortality in patients with this manifestation of PAD [53].

The high 1-year mortality of around 20–25 % in patients with CLI [7, 21, 22, 52] is mainly due to cardiovascular disease. Furthermore, this already high mortality rate is increased even more in patients with features of inflammation, such as increased leukocyte count and fibrinogen level [23], or an elevated neutrophil/lymphocyte ratio and increased troponin levels [54]. The inflammatory mediators IL-6, TNFα, neopterin, and hs-CRP have also been associated with 1-year mortality in subjects with CLI [53]. For TNFα and neopterin, this association was independent of other variables, such as age, sex, gangrene, lipid-lowering therapy, leukocyte count, renal function, and HDL cholesterol. As the relationships between inflammatory mediators and mortality persisted after exclusion of patients with gangrene, these relationships may only partly be explained by the fact that patients with inflammatory processes such as gangrene of the extremities showed a high mortality [53]. Furthermore, when the patient material was later analyzed concerning 5- and 10-year mortality, the predictive value of TNFα at diagnosis persisted (Fig. 13.2). Data are partly conflicting, however, as no associations were found among α-defensin, hs-CRP, and mortality in CLI patients in the above-mentioned study by Urbonaviciene and co-workers [52].