This review shows the great improvement in PAD management due to percutaneous treatment. Actually, even if all the techniques discussed below have a good therapeutic impact in terms of regression of LE-PAD as well as in term of days of recovery, they all suffer of an important limitation, the restenosis of the treated area. This drawback is reported in up to 60% of primarily successful PTA [
33]. Regardless of the type of intervention, stenosis or restenosis develops in a significant number of patients, often leading to limb loss or death and it remains the “Achille’s heel” of the application of these procedures. Restenosis is arbitrarily defined as a greater than 50% narrowing of vessel diameter compared with a reference artery. The clear mechanism of restenosis is not perfectly known but several evidences suggest a strong link between restenosis itself and vessel inflammation. This theory is feeding the interest toward the identification of makers of inflammations, which may have a diagnostic but especially prognostic role in the managing of the vessels restenosis. The plasma proteins, C-reactive protein (CRP), serum amyloid A (SAA), and fibrinogen are sensitive, specific, and fast reacting markers of acute phase reaction [
34] and provide an indirect measure of a cytokine dependent inflammatory process of the arterial wall [
35]. Restenosis is mainly due to excessive neointima formation [
12]. Percutaneous intervention leads to mechanical injury that induces vascular inflammation, which stimulates vascular smooth muscle cell proliferation and extracellular matrix deposition, resulting in neointimal thickening and restenosis [
36]. It has been demonstrated that in a rat model of carotid artery dilation by a balloon catheter, the first step in allowing vascular smooth muscle cell (SMC) proliferation from the tunica media to the intima is the occurrence of internal elastic lamina (IEL) rupture [
12]. During arterial catheterization, the endothelial layer is removed by balloon dilation, resulting in the loss of this important anti-thrombogenic layer. Moreover, endothelial denudation results in the exposure of the subendothelial matrix to flowing blood. Platelets and fibrinogen immediately adhere to the surface of the injured vessel, inducing platelets aggregation and activation. Activated platelets release various cytokines, chemokines, and growth factors, which initiate smooth muscle cell (SMC) proliferation and leukocyte recruitment to the injured vessel segment. Substances released or activated after injury include platelet-derived growth factor (PDGF), transforming growth factor (TGF)-β, interleukin (IL)-1, IL-6, IL-8, thrombin, adenosine diphosphate, and thromboxane A2 [
33,
37]. The initial tethering and rolling of leukocytes on platelets is mediated through binding of the leukocyte receptor P-selectin glycoprotein ligand-1 to platelet P-selectin. Rolling leukocytes stop and firmly attach to adherent platelets when the leukocyte integrin Mac-1 (CD11b/CD18) binds to platelet glycoprotein Ib-alpha or to fibrinogen bound to the platelet glycoprotein IIb/IIIa [
36]. After, there is smooth muscle cell (SMC) proliferation and migration to the intima. Migrated smooth muscle cells (SMCs) contribute to the intimal thickening by the excessive synthesis of extracellular matrix (ECM) and proliferation. Intimal SMCs are derived primarily from the media, but they may also be derived from adventitial myofibroblasts, pericytes associated with infiltrating microvessels, and circulating progenitor cells. The pathway for SMC proliferation is an integrated mechanism involving several known and as yet unidentified cell-signalling pathways coupled to the cell cycle. Peptides binding to tyrosine kinase receptors are possibly the most potent mitogens for smooth muscle cells (SMCs) and they modulate a variety of signalling pathways, including ras [
38], raf, the mitogen activated protein kinase (MAPK) cascade, the phosphoinositol-3 kinase- protein kinase B pathway and the diacylglycerol protein kinase C pathway [
35,
39,
40]. It was previously described the opposite effects of SMCs proliferation of two intracellular pathways. In fact, it was showed that the stimulation of Ras-MAPKs proteins induces the proliferation of SMCs [
38,
34] that are, in contrast, inhibited by the activation of cAMP-PKA signaling [
41,
42]. Furthermore hyperinsulinemia, through activation of the ras–MAPK pathway, rather than hyperglycemia per se, appears to be crucial in determining the exaggerated neointimal response after balloon angioplasty in diabetic animals [
43]. Moreover, new growing knowledge about molecular mechanism of restenosis highlight the role of micro-RNA in vascular remodeling [
44].
Several studies show the rate of restenosis after baloon angioplasty, after stent implantation and after atherectomy using different types of devices. Ablative therapy deserves particular relevance and several studies have investigated the rates of occurrence of restenosis after debulking procedures. TALON (Treating Peripherals with Silver Hawk Outcome Collections) study involved 601 patients showing a rate of survival free of TLR at 6 months of 90% and at 12 months of 80% [
25]. Sarac et al. recruited 167 patients treated with Silver Hawk device in tibial arteries. Cumulative 1-year primary and secondary patency rates were 43% and 57%, respectively [
45]. An interesting result comes from Shammas et al. trial which demonstrates the inferiority of Silver Hawk atherectomy versus balloon angioplasty. In this trial 72 patients were divided in two groups. The first group (n=38) were treated with Silver Hawk atherectomy, the second group (n=35) were treated with conventional balloon angioplasty. Primary patency at 2 months was of 34% in the first group versus 56% in the second group [
46]. Another kind of device was investigated from Scheiner et al. who studied the impact of Laser ablative atherectomy in SFA arteries. They reported their experience with the excimer laser in recanalizing occluded SFA arteries: the technical success was 90.5%, but primary patency at 1 year was only 33.6%. The 1 year assisted primary and secondary patency rates were 65.1% and 75.9%, respectively. In addition, short SFA occlusions (1–10 cm) treated with the excimer laser demonstrated primary, assisted primary, and secondary patency rates of 49.2%, 76.5%, and 86.3%, respectively, at 36-month follow-up [
47]. Stoner et al. reported their data on 40 patients treated with laser atherectomy; average follow-up was 461±49 days. The indication for laser atherectomy was critical limb ischemia in 26 (65%) and claudication in 11 (35%) patients. A total of 47 lesions in the femoropopliteal and infrapopliteal arterial segments were treated. Adjunctive angioplasty was used in 75% of cases. The overall 12 month primary patency was 44% [
48]. Two further trials investigated rotational atherectomy: Myers et al. treated 72 patients using rotablator and showed a primary patency of 47% at 6 months, 31% at 12 months and of 18,5% at 24 months [
49]. In the OASIS TRIAL, rotational atherectomy with Diamondback 360° was associated with a rate of TLR of 0,9% at 6 months, but further data are needed to understand the impact of this device on long term patency.