Form Of Peripheral Arterial Disease Research Articles

Medical management of critical limb ischaemia: where do we stand today?

Critical limb ischaemia (CLI) is a severe form of peripheral arterial disease (PAD). CLI often causes disabling symptoms of pain and can lead to loss of the affected limb. It is also associated with increased risk of myocardial infarction, stroke and death from cardiovascular disease. The 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. Here, current evidence regarding the medical management of CLI is reviewed. Cardiovascular risk factors should be assessed in all patients with CLI; smoking cessation and treatment of hypertension, hyperlipidaemia and diabetes all reduce the mortality rate in those with PAD. Antiplatelet agents (either aspirin or clopidogrel) are recommended to reduce both the incidence of cardiovascular events and risk of arterial occlusion. By contrast, routine use of anticoagulation (either warfarin or heparin) is not recommended. Treatment of the limbs themselves is often more challenging. Prostanoids may have some efficacy for treating rest pain and for ulcer healing, and iloprost shows favourable results in reducing the risk of major amputations, but long-term follow-up data regarding disease progression are lacking. There is insufficient evidence to support the use of naftidrofuryl or cilostazol, and pentoxifylline is not beneficial. Furthermore, there is no evidence of proven benefit of hyperbaric oxygen. A number of angiogenic growth factors have been studied in Phase I studies and randomized controlled trials (RCTs). They appear to be safe, but efficacy results have been mixed. Treatment with stem cells also shows some potential from early trials, but further larger RCTs are needed to demonstrate clear benefit. Thrombolysis may be an alternative for patients who develop acute limb ischaemia and are unsuitable for surgical intervention. However, newer endovascular techniques are likely to have a greater role in the future.

Therapeutic angiogenesis in critical limb ischemia.

Critical limb ischemia (CLI) is a severe form of peripheral artery disease associated with high morbidity and mortality. The primary therapeutic goals in treating CLI are to reduce the risk of adverse cardiovascular events, relieve ischemic pain, heal ulcers, prevent major amputation, and improve quality of life (QoL) and survival. These goals may be achieved by medical therapy, endovascular intervention, open surgery, or amputation and require a multidisciplinary approach including pain management, wound care, risk factors reduction, and treatment of comorbidities. No-option patients are potential candidates for the novel angiogenic therapies. The application of genetic, molecular, and cellular-based modalities, the so-called therapeutic angiogenesis, in the treatment of arterial obstructive diseases has not shown consistent efficacy. This article summarizes the current status related to the management of patients with CLI and discusses the current findings of the emerging modalities for therapeutic angiogenesis.

Nanoparticle-Mediated Delivery of Pioglitazone Enhances Therapeutic Neovascularization in a Murine Model of Hindlimb Ischemia

Critical limb ischemia is a severe form of peripheral artery disease (PAD) for which neither surgical revascularization nor endovascular therapy nor current medicinal therapy has sufficient therapeutic effects. Peroxisome proliferator activated receptor-γ agonists present angiogenic activity in vitro; however, systemic administration of peroxisome proliferator-activated receptor-γ agonists is hampered by its side effects, including heart failure. Here, we demonstrate that the nanoparticle (NP)-mediated delivery of the peroxisome proliferator activated receptor-γ agonist pioglitazone enhances its therapeutic efficacy on ischemia-induced neovascularization in a murine model. In a nondiabetic murine model of hindlimb ischemia, a single intramuscular injection of pioglitazone-incorporated NP (1 µg/kg) into ischemic muscles significantly improved the blood flow recovery in the ischemic limbs, significantly increasing the number of CD31-positive capillaries and α-smooth muscle actin-positive arterioles. The therapeutic effects of pioglitazone-incorporated NP were diminished by the peroxisome proliferator activated receptor-γ antagonist GW9662 and were not observed in endothelial NO synthase-deficient mice. Pioglitazone-incorporated NP induced endothelial NO synthase phosphorylation, as demonstrated by Western blot analysis, as well as expression of multiple angiogenic growth factors in vivo, including vascular endothelial growth factor-A, vascular endothelial growth factor-B, and fibroblast growth factor-1, as demonstrated by real-time polymerase chain reaction. Intramuscular injection of pioglitazone (1 µg/kg) was ineffective, and oral administration necessitated a >500 μg/kg per day dose to produce therapeutic effects equivalent to those of pioglitazone-incorporated NP. NP-mediated drug delivery is a novel modality that may enhance the effectiveness of therapeutic neovascularization, surpassing the effectiveness of current treatments for peripheral artery disease with critical limb ischemia.

Angiogenic potential of clonal populations of human mesenchymal stem cells

Critical Limb Ischemia (CLI) is the most severe form of peripheral arterial disease. It is a highly prevalent condition with suboptimal therapeutic options. One third of CLI patients are not suitable for surgical revascularization - these 'no-option' patients have substantial morbidity and mortality and frequently have diabetes mellitus. Hence, new treatments are urgently required. Mesenchymal Stem Cells (MSCs) are a novel and exciting potential for inducing therapeutic angiogenesis. However, MSCs are heterogeneous in nature and the angiogenic potential of different clonal populations from the same donor is currently unknown. We hypothesize that MSC heterogeneity will allow for the isolation of clonal cell populations with enhanced angiogenic potential. These populations may have enhanced therapeutic potential and may also be of interest in exploring the mechanism of MSC-induced angiogenesis.

Role and Management of Coagulation Disorders in Peripheral Arterial Disease

Peripheral arterial disease (PAD) has often underlying risk factors, of which diabetes and cigarette smoking are the most common. Enhanced platelet activation and interaction with vessel wall associate with atherothrombotic disease, but also increased fibrinogen levels, thrombin generation and fibrin turnover are typical for PAD. The pathogenic role of fibrinogen, thrombin formation and fibrin degradation is suggested not only in acute thrombotic complications, but also in the stable form of PAD, where these markers associate with the functional severity (ankle-brachial blood pressure index). The coagulation-specific etiologies of PAD should be suspected if the atherothrombotic disease has severe manifestations, especially while the traditional risk factors are absent, or if the patient has also a history of venous thromboembolism. Malignant disease may be present in form of peripheral arterial thrombosis as well. Thrombophilia may expose patients to idiopathic thrombosis--both spontaneously and after vascular interventions. The management of these patients includes often combination therapies with antiplatelet agents and anticoagulants. Obviously, the strict policy to avoid risk factors and to treat them well in avoidance of progression of arterial disease is highly important. In the absence of published follow-up data the evidence to support the management strategies is weak and individual tailoring of efficacious and safe antithrombotic drug therapy remains our challenge. These patients benefit from continuous medical attention by the experts in the field of angiology. Management of PAD is an excellent example of the multidisciplinary approach where the hematologist meets the vascular surgeon or interventional radiologist to secure the best available patient care.

Prognostic Usefulness of Clinical and Subclinical Peripheral Arterial Disease in Men With Stable Coronary Heart Disease

The prognostic value of symptomatic peripheral arterial disease (PAD) in patients with coronary heart disease (CHD) is well documented, but few reports differentiating between symptomatic and asymptomatic forms of PAD are available. We investigated the respective prognostic effect of clinical and subclinical PAD on long-term all-cause mortality in patients with stable CHD. We analyzed 710 patients with stable CHD referred for hospitalization for CHD evaluation and management. As a part of the study, they completed questionnaires on medical history, underwent a standardized clinical examination, including ankle-brachial index (ABI) measurement, and provided a fasting blood sample. Three groups of patients were individualized: no PAD (no history of PAD and ABI >0.9 but ≤1.4); subclinical PAD (no history of PAD but abnormal ABI [i.e., ≤0.9 or >1.4); and clinical PAD (history of claudication, peripheral arterial surgery, or amputation due to PAD). Clinical and subclinical PAD was present in 83 (11.7%) and 181 (25.5%) patients, respectively. After a median follow-up of 7.2 years, 130 patients died. On multivariate analysis adjusted for age, hypertension, diabetes, dyslipidemia, smoking, left ventricular ejection fraction, CHD duration, heart rate, history of stroke or transient ischemic attack, and coronary revascularization, previous clinical PAD (hazard ratio 2.11, 95% confidence interval 1.28 to 3.47) and subclinical PAD (hazard ratio 1.65, 95% confidence interval 1.11 to 2.44) were significantly associated with increased all-cause mortality. In conclusion, our study has demonstrated that the detection of subclinical PAD by ABI in patients with stable CHD provides additional information for long-term mortality risk evaluation.

Relationship Between High-Sensitivity C-Reactive Protein and Risk Factors in Patients With Peripheral Arterial Disease—A Cross-Sectional Study

We investigated whether patients with peripheral arterial disease (PAD) with various serum levels of high-sensitivity C-reactive protein (hsCRP) differ in the frequency of atherosclerotic risk factors. Among 388 patients, hsCRP levels were (1) low, <1 mg/L, in 41 (10.6%) participants; (2) medium, from 1 to 3 mg/L, in 152 (39.2%) participants, and (3) high, >3 mg/L, in 195 (50.2%) individuals. According to multivariate logistic regression analysis, in comparison with patients with hsCRP level ≤3.0 mg/L, those with higher hsCRP levels had more frequently a severe form of PAD (gangrene, P ranged from .045 to <.001; ankle-brachial index ≤.40, P = .059) and had more frequently some of atherosclerotic risk factors (metabolic syndrome, P = .007; hypertension, P = .013; abdominal obesity, P = .007; high levels of uric acid, P = .022; high level of fibrinogen, P < .001; and depression, P = .015).

Abstract P250: Incidence of Hospitalized Peripheral Arterial Disease and Critical Limb Ischemia: The Atherosclerosis Risk in Communities (ARIC) Study

Introduction: Lower extremity peripheral arterial disease (PAD) affects between 12% and 20% of Americans over the age of 65. PAD compromises quality of life, contributes a high burden of disability and its related health care costs exceed $4 billion/year, yet this preventable CVD outcome remains understudied. Aims: Assess the incidence of hospitalized PAD, and of the most severe form of PAD, critical limb ischemia (CLI), in middle-aged men and women, and evaluate their risk factors in a bi-ethnic, population-based cohort. We hypothesized that incidence of hospitalized PAD and CLI are higher in African Americans, and that modifiable atherosclerosis risk factors in middle age predict these sequelae of PAD. Methods: We analyzed data from 13,865 participants from the Atherosclerosis Risk in Communities Study aged 45–64 without PAD at baseline (1987–89). Incident PAD and CLI events were identified using ICD-9 codes from active surveillance of all hospitalizations among cohort participants from 1987 through 2008. All estimates are incidence rates per 10,000 person-years; nominal statistical significance was achieved for all baseline characteristic comparisons reported. Results: There were 707 incident hospitalized PAD during a median of 18 years of follow-up (249,570 person-years). The overall age-adjusted incidence of PAD and limb-threatening CLI were 26.0 and 9.6 per 10,000 person-years, respectively. Incidence of hospitalized PAD was higher in African Americans than whites (34.7 vs. 23.2) and in men compared to women (32.4 vs. 26.7). Baseline characteristics associated with age-adjusted incident PAD (per 10,000 person-years) compared to their referent groups were diabetes (91.2 vs. 19.0), history of smoking (33.6 vs. 16.2), hypertension (42.6 vs. 18.6), coronary heart disease (81.4 vs. 24.1), and obesity (41.5 vs. 20.2). Incidence of CLI also was higher among African Americans (21.0 vs. 5.9) and in men (10.5 vs. 8.9 per 10,000 person-years). Baseline characteristics associated with incident CLI were similar to those for PAD. Conclusions: The absolute risk of hospitalized lower extremity PAD in this community-based cohort is of a magnitude similar to that of heart failure and of stroke. As modifiable factors are strongly predictive of the long-term risk of hospitalized PAD and CLI, particularly among African Americans, our results highlight the need for effective risk factor prevention and control.

Health related quality of life in patients with critical limb ischemia

Critical limb ischemia (CLI) is the terminal stage of peripheral artery disease. Research in recent years has been largely focussed on treatment options such as bypass surgery / endovascular treatment, surgery / primary amputation and additional benefits of supportive pharmacotherapy. Despite this plethora of treatment options, however, patients continue to have a reduced health related quality of life (HRQoL). Aim of the present work was to review the available evidence of improvement of HRQoL with regard to different treatment options. We found that a number of clinical studies have been conducted using HRQoL measures mostly as secondary outcomes in patients with CLI and other less severe forms of peripheral arterial disease. The studies demonstrate a consistent improvement of HRQoL over baseline within the first few months after the intervention. Prostaglandins, but no other pharmacotherapies, appear to be effective in patients without an option for revascularization. Due to a largely differing patient population under investigation and the different degrees of disease progression it appears difficult however to compare different treatment options with respect to their impact on HRQoL. HRQoL improvement as a predefined endpoint of novel therapeutic approach studies should be considered more consequently.

Current State of Diagnosis and Management of Critical Limb Ischemia

Critical limb ischemia represents the most severe form of peripheral arterial disease and carries with it severe morbidity and mortality risks. Because of comorbidity risks, early diagnosis and aggressive medical management make up an important part of the treatment paradigm for these individuals. However, in addition to managing these comorbid conditions, the physician caring for these individuals must be able to provide revascularization options that will improve arterial flow to the threatened extremity and assure healing of complicated wounds. Both open surgical and endovascular therapies have proven beneficial in restoring flow to severely ischemic limbs in these patients. Additionally, combinations of the above therapeutic methods have offered more available options for these patients. This article reviews care of patients with critical limb ischemia with critical assessment of options for medical and revascularization options.

Invited commentary

The increasingly aggressive endovascular management of tibial artery occlusive disease is understandable given the fact that endovascular surgeons have routinely acquired increased technical skill and gained access to enabling endovascular hardware. However, the many options available to treat atheromatous lesions, including balloon angioplasty, cryoplasty, excisional atherectomy, rotational atherectomy, self-expanding stent placement, covered stent placement, balloon expandable stent placement, and drug-eluting stent placement, have driven the treatment of lesions faster than data has provided guidance. Unlike trials of the use of drug-eluting stents in the superficial femoral artery in which no benefit was noted,1Duda S.H. Bosiers M. Lammer J. Scheinert D. Zeller T. Tielbeek A. et al.Sirolimus-eluting versus bare nitinol stent for obstructive superficial femoral artery disease: the SIROCCO II trial.J Vasc Interv Radiol. 2005; 16: 331-338Abstract Full Text Full Text PDF PubMed Scopus (395) Google Scholar, 2Duda S.H. Bosiers M. Lammer J. Scheinert D. Zeller T. Oliva V. et al.Drug-eluting and bare nitinol stents for the treatment of atherosclerotic lesions in the superficial femoral artery: long-term results from the SIROCCO trial.J Endovasc Ther. 2006; 13: 701-710Crossref PubMed Scopus (445) Google Scholar the authors of the Drug Eluting Stents In the Critically Ischemic Lower Leg (DESTINY) trial provide us with level I evidence to support the use of drug-eluting stents over bare-metal stents in the management of tibial arterial lesions. Interestingly, a similar report has been published in an electronic format since the editorial process began on this article.3Rastan A. Tepe G. Krankenberg H. Zahorsky R. Beschorner U. Noory E. et al.Sirolimus-eluting stents vs. bare-metal stents for treatment of focal lesions in infrapopliteal arteries: a double-blind, multi-centre, randomized clinical trial.Eur Heart J. 2011; 32: 2274-2281Crossref PubMed Scopus (164) Google Scholar Results are surprisingly similar, with primary patency rates of 80.6% for sirolimus-eluting stents deployed in tibial arteries and 55.6% for lesions treated with bare-metal stents (P =.004) vs the 85% and 54% noted in this study. There is a distinct historical parallel between this increasingly aggressive endovascular treatment of tibial disease and the surgical treatment of tibial disease in the mid-1980s, when bypass grafts were performed both with autogenous vein and with prosthetic conduits. Data from carefully performed clinical trials demonstrated the superiority of autogenous conduit use and thus defined a standard of care.4Bergan J.J. Veith F.J. Bernhard V.M. Yao J.S. Flinn W.R. Gupta S.K. et al.Randomization of autogenous vein and polytetrafluorethylene grafts in femoral-distal reconstruction.Surgery. 1982; 92: 921-930PubMed Google Scholar, 5Veith F.J. Gupta S.K. Ascer E. White-Flores S. Samson R.H. Scher L.A. et al.Six-year prospective multicenter randomized comparison of autologous saphenous vein and expanded polytetrafluoroethylene grafts in infrainguinal arterial reconstructions.J Vasc Surg. 1986; 3: 104-114PubMed Scopus (944) Google Scholar Similarly, a new standard has been set with respect to the use of drug-eluting stents in the tibial arteries. Many basic questions remain unanswered, however. The most fundamental is how the use of stents fits into the overall scheme of the endovascular management of tibial vessel occlusive disease. The effectiveness of a strategy involving the use of drug-eluting stents vs angioplasty alone, atherectomy, or any other adjunctive measure remains untested. Furthermore, although the endovascular surgeon can now treat tibial artery lesions with drug-eluting stents and can point to specific data to support this approach, this study has important limitations that limit its generalizability. The lesions treated in this study were <40 mm in length, which, of course, represents a relatively small subset of the patients with treatable tibial disease. An intervention to improve the outcomes of recanalization of long tibial segments remains elusive. We are in the infancy of our understanding of the best means of treating tibial vessel occlusive disease, but we now have some level I data to guide our decision making. However, of all of the treatment paradigms for the management of tibial disease, this may be the most expensive. Further research will help define the cost-effectiveness of this approach. The next step in the evolution of our understanding of the most appropriate treatment of tibial disease will compare the use of drug-eluting stents vs other available technologies, such as balloon angioplasty and atherectomy, for lesions suitable for endovascular treatment. Randomized comparison of everolimus-eluting versus bare-metal stents in patients with critical limb ischemia and infrapopliteal arterial occlusive diseaseJournal of Vascular SurgeryVol. 55Issue 2PreviewCritical limb ischemia, the most severe form of peripheral arterial disease, results in extremity amputation if left untreated. Endovascular recanalization of stenotic or occluded infrapopliteal arteries has recently emerged as an effective form of therapy, although the duration of patency is typically limited by restenosis. Recently, it has been suggested that drug-eluting stents originally developed for the coronary arteries might also be effective in preventing restenosis in the infrapopliteal arteries. 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Toll-Like Receptors in Ischaemia and Its Potential Role in the Pathophysiology of Muscle Damage in Critical Limb Ischaemia

Toll-like receptors (TLRs) are key receptors of the innate immune system which are expressed on immune and nonimmune cells. They are activated by both pathogen-associated molecular patterns and endogenous ligands. Activation of TLRs culminates in the release of proinflammatory cytokines, chemokines, and apoptosis. Ischaemia and ischaemia/reperfusion (I/R) injury are associated with significant inflammation and tissue damage. There is emerging evidence to suggest that TLRs are involved in mediating ischaemia-induced damage in several organs. Critical limb ischaemia (CLI) is the most severe form of peripheral arterial disease (PAD) and is associated with skeletal muscle damage and tissue loss; however its pathophysiology is poorly understood. This paper will underline the evidence implicating TLRs in the pathophysiology of cerebral, renal, hepatic, myocardial, and skeletal muscle ischaemia and I/R injury and discuss preliminary data that alludes to the potential role of TLRs in the pathophysiology of skeletal muscle damage in CLI.

Randomized comparison of everolimus-eluting versus bare-metal stents in patients with critical limb ischemia and infrapopliteal arterial occlusive disease

Critical limb ischemia, the most severe form of peripheral arterial disease, results in extremity amputation if left untreated. Endovascular recanalization of stenotic or occluded infrapopliteal arteries has recently emerged as an effective form of therapy, although the duration of patency is typically limited by restenosis. Recently, it has been suggested that drug-eluting stents originally developed for the coronary arteries might also be effective in preventing restenosis in the infrapopliteal arteries. This prospective, randomized, controlled clinical trial tested the hypothesis that treatment of infrapopliteal arterial occlusive lesions with an everolimus-eluting stent (Xience V) would provide superior patency to treatment with a bare-metal stent (Multi-Link Vision). A sample size of 140 patients was planned to be enrolled at five European investigative sites. The primary end point was arterial patency at 12 months, defined as the absence of ≥50% restenosis based on quantitative analysis of contrast angiography. Between March of 2008 and September of 2009, 74 patients were treated with Xience V and 66 patients were treated with Vision. After 12 months, the primary patency rate after treatment with Xience V was 85% compared with 54% after treatment with Vision (P = .0001). Treatment with Xience V significantly reduced mean in-stent diameter stenosis (21% ± 21% vs 47% ± 27%; P < .0001) and mean in-stent late lumen loss (0.78 ± 0.63 vs 1.41 ± 0.89 mm; P = .001). There were no differences in the percentage of patients receiving a designation of Rutherford class 0 or 1 at the 12-month follow-up visit (56% for Vision, vs 60% for Xience V; P = .68). Major extremity amputations were rare in both groups (two for Vision and one for Xience V). The use of the Xience V stent significantly reduced the need for repeat intervention: freedom from target lesion revascularization was 91% for Xience V vs 66% for Vision (P = .001). Treatment of the infrapopliteal occlusive lesions of critical limb ischemia with everolimus-eluting stents reduces restenosis and the need for reintervention compared with bare metal stents.

High Leg Salvage Rate after Infrainguinal Bypass Surgery for Ischemic Tissue Loss (Fontaine IV) is Compromised by the Short Life Expectancy

Most studies analysing the prognosis of infrainguinal bypass surgery (IBS) in patients with critical leg ischemia (CLI) have combined the outcome of patients with rest pain and tissue loss. The aim of the present study was to evaluate amputation-free survival (AFS) after IBS in patients with the most advanced form of peripheral arterial disease, CLI with tissue loss (Fontaine IV), and to analyse the risk factors for an adverse outcome. 636 patients with CLI and tissue loss who underwent unilateral IBS between January 2000 and December 2006 at our institution were included in this retrospective study. At one year, the leg salvage, survival and amputation-free survival rates were 83%, 71% and 55%, respectively, and at five years 76%, 38% and 30%, respectively. In univariate analysis, diabetes was associated with decreased AFS. In multivariate analysis, age, coronary artery disease, chronic pulmonary disease, gangrene and renal insufficiency were independent risk factors for decreased AFS. Infrainguinal bypass grafting results in a high rate of leg salvage. Amputation-free survival was low during the follow-up due to the high mortality of patients with CLI and tissue loss. Several co-morbidities of the CLI patients were associated with decreased amputation-free survival.

Quality of life in patients with no-option critical limb ischemia underlines the need for new effective treatment

To provide a solid baseline reference for quality of life (QoL) in patients with no-option critical limb ischemia (CLI). CLI is associated with surgery, endovascular interventions, hospitalization, and a poor prognosis. An increasing number of clinical trials are, therefore, investigating new treatment strategies (eg, therapeutic neovascularization) in patients with CLI. QoL serves as an important secondary endpoint in many of these trials, but solid reference QoL data for patients with no-option CLI are lacking. The Medical Outcomes Study Short Form 36 (SF-36) and the EuroQol-5D (EQ-5D) questionnaires were used to obtain baseline QoL scores from 47 patients with no-option CLI participating in a therapeutic neovascularization trial. To allow for easy comparability, a norm-based scoring (NBS) method was used to report the results of the SF-36. Scores of patients with CLI were furthermore compared with scores of patients with milder forms of peripheral arterial disease (PAD) and with patients with cardiovascular risk factors only. Determinants of QoL in patients with PAD were identified using multiple linear regression methods. Patients with no-option CLI reported QoL scores below the general population mean on every health dimension of the SF-36. Physical functioning, role physical functioning, and bodily pain were affected most intensively. These poor physical QoL scores were further underlined when compared with other patients with milder forms of PAD or patients with cardiovascular risk factors only. Patients with CLI scored poorly on the pain/discomfort and the usual activities domain of the EQ-5D. Diabetes, female gender, body mass index, and the ankle-brachial index at rest were significant determinants of the QoL in PAD on multivariate analysis. The QoL data of patients with no-option CLI using NBS methods for the SF-36 provide a baseline reference for ongoing clinical trials on new treatment strategies. Our data stress the need for new revascularization therapies in patients with no-option CLI.

Understanding Objective Performance Goals for Critical Limb Ischemia Trials

Critical limb ischemia (CLI), the most advanced form of peripheral arterial disease, is associated with a high rate of limb loss and substantial mortality. Revascularization remains the cornerstone of limb salvage in the CLI patient, and surgical bypass is the established standard. Endovascular therapies, such as angioplasty, atherectomy, and stenting offer a less-invasive option, but evidence of efficacy is lacking, and no devices are currently approved specifically for CLI. Design and execution of clinical trials in the CLI population are challenging, in part because of the lack of consensus on cohort definitions and relevant endpoints. Recently, the Society for Vascular Surgery undertook an initiative to define therapeutic benchmarks, objective performance goals (OPGs), for CLI. Using surgical bypass with autogenous vein as the standard for comparison, OPGs were developed for nine safety and efficacy measures that could be utilized in the premarket assessment of new devices in CLI. Data from three large randomized controlled trials of surgical bypass for CLI were analyzed. We defined a major adverse limb event (MALE) as a key endpoint for revascularization therapies in CLI--inclusive of amputation (transtibial or above) or any major vascular reintervention (thrombectomy, thrombolysis, or major surgical procedure [new bypass graft, jump/interposition graft revision]) in the index limb. Freedom from perioperative (30-day) death or any MALE (MALE + POD) was suggested as the primary efficacy endpoint for a single-arm trial design in CLI, with an observed rate of 76.9% for the surgical bypass controls at 1 year. Specific high-risk subgroups were also defined from the surgical dataset--based on clinical (age older than 80 years and tissue loss), arterial anatomy (infrapopliteal disease), and conduit quality (inadequate saphenous vein) characteristics. Risk-adjusted OPG were developed for these subgroups of interest. These OPGs define a new set of benchmarks for assessing the performance of revascularization therapies in CLI, and should facilitate clinical trial design and device development in this arena.

Critical limb ischemia.

Opinion statementCritical limb ischemia (CLI), defined as chronic ischemic rest pain, ulcers, or gangrene attributable to objectively proven arterial occlusive disease, is the most advanced form of peripheral arterial disease. Traditionally, open surgical bypass was the only effective treatment strategy for limb revascularization in this patient population. However, during the past decade, the introduction and evolution of endovascular procedures have significantly increased treatment options. In a certain subset of patients for whom either surgical or endovascular revascularization may not be appropriate, primary amputation remains a third treatment option. Definitive high-level evidence on which to base treatment decisions, with an emphasis on clinical and cost effectiveness, is still lacking. Treatment decisions in CLI are individualized, based on life expectancy, functional status, anatomy of the arterial occlusive disease, and surgical risk. For patients with aortoiliac disease, endovascular therapy has become first-line therapy for all but the most severe patterns of occlusion, and aortofemoral bypass surgery is a highly effective and durable treatment for the latter group. For infrainguinal disease, the available data suggest that surgical bypass with vein is the preferred therapy for CLI patients likely to survive 2 years or more, and for those with long segment occlusions or severe infrapopliteal disease who have an acceptable surgical risk. Endovascular therapy may be preferred in patients with reduced life expectancy, those who lack usable vein for bypass or who are at elevated risk for operation, and those with less severe arterial occlusions. Patients with unreconstructable disease, extensive necrosis involving weight-bearing areas, nonambulatory status, or other severe comorbidities may be considered for primary amputation or palliative measures.

Relationship between sociodemographic, anthropometric and biochemical characteristics and degree of peripheral arterial disease

Peripheral arterial disease (PAD) is a severe atherosclerotic condition. The relationship between various risk factors and severity of PAD, measured by Ankle Brachial Index (ABI), has been the subject of a relatively small number of studies. The aim of the present study was to investigate whether there was any relationship between severity of PAD, expressed as ABI, and anthropometric, clinical and biochemical characteristics of patients, including inflammatory markers. The cross-sectional study, involving 388 consecutive patients with verified PAD, was performed at the Dedinje Vascular Surgery Clinic in Belgrade. The diagnosis of PAD was defined by Doppler sonography as ABI < 0.9, and by symptoms. Data on cardiovascular risk factors, anthropometric parameters, clinical and biochemical characteristics were collected for all participants. In the analysis, chi2 test, t-test and multivariate logistic regressions were used. According to the results of multivariate analysis (the model of which included age, percentage of body fat, average value of uric acid, high sensitivity C-reactive protein--hsCRP > or = 3 mg/L, fibrinogen > or = 4 g/L, Baecke index of physical activity at work and Baecke index of leisure-time physical activity), the patients with more severe form of peripheral arterial disease (ABI < or = 0.40) had more frequently increased high sensitivity C-reactive protein (p = 0.002), lower Baecke index of physical activity at work (p = 0.050) and lower Baecke index of leisure-time physical activity (p = 0.024). Average value of body fat was significantly higher in the patients with a less severe form of disease (p = 0.006). According to the results obtained, the increased values of hsCRP and physical inactivity are associated with a more severe form of PAD (ABI < or = 0.40).

Therapeutic Angiogenesis in the Management of Critical Limb Ischemia

Critical limb ischemia (CLI) represents the most severe form of peripheral arterial disease. Manifestations of CLI include rest pain, ischemic ulcers, and/or gangrene. The presence of CLI frequently leads to amputation, and furthermore, patients with CLI are at an increased risk of cardiovascular events including death. Treatment options for CLI when revascularization is not possible are extremely limited. Therapeutic angiogenesis is a promising new tool in the management of CLI. There is a growing body of evidence demonstrating the safety and efficacy of therapeutic angiogenesis with gene and cell therapy. Many factors must be considered in formulating clinically efficacious gene and/or cell therapies. The dosing regimen, route of delivery, and choice of growth factor or cell population must be decided. Although the optimal regimen of therapeutic angiogenesis has yet to be identified, building on the knowledge gained from the early pioneering studies may help to identify the best combination.

The Association of Active and Passive Smoking with Peripheral Arterial Disease: Results from NHANES 1999–2004

We aim to quantify the association between different forms of tobacco use and peripheral arterial disease (PAD) and to characterize the association between secondhand smoke exposure and PAD in a large nationally representative sample of the US population. We observed significant associations between current and former cigarette smoking and PAD. The association between noncigarette forms of tobacco and PAD was not significant even after adjustment for clinical and demographic variables. Secondhand smoke was not significantly associated with PAD. Interestingly, a ;;threshold phenomenon'' for tobacco exposure was demonstrated for PAD occurrence. Individuals with serum cotinine >155 ng/ mL were at significantly higher risk of having PAD as compared with a nonexistent or a minimal risk below this threshold value. Lack of association between PAD and secondhand smoke exposure in conjunction with the threshold phenomenon described above leads us to speculate existence of striking differences between the systemic circulation and lower extremity vasculature in terms of pathogenesis of atherosclerosis.