Peripheral arterial disease (PAD) - A challenging manifestation of atherosclerosis.

The diagnosis of peripheral arterial disease (PAD) is not always evident as symptoms and signs may show great variation. As all grades of PAD are linked to both an increased risk for cardiovascular complications and adverse limb events, awareness of the condition and knowledge about diagnostic measures, prevention and treatment is crucial. This article presents in a condensed form information on PAD and its management.

Editor's choice. A randomized controlled trial of the fascia suture technique compared with a suture-mediated closure device for femoral arterial closure after endovascular aortic repair.

OBJECTIVES: The aim was to investigate whether the fascia suture technique (FST) can reduce access closure time and procedural costs compared with the Prostar technique (Prostar) in patients undergoing endovascular aortic repair and to evaluate the short- and mid-term outcomes of both techniques. METHODS: In this two center trial, 100 patients were randomized to access closure by either FST or Prostar between June 2006 and December 2009. The primary endpoint was access closure time. Secondary outcome measures included access related costs and evaluation of the short- and mid-term complications. Evaluation was performed peri- and post-operatively, at discharge, at 30 days and at 6 months follow up. RESULTS: The median access closure time was 12.4 minutes for FST and 19.9 minutes for Prostar (p < .001). Prostar required a 54% greater procedure time than FST, mean ratio 1.54 (95% CI 1.25-1.90, p < .001) according to regression analysis. Adjusted for operator experience the mean ratio was 1.30 (95% CI 1.09-1.55, p = .005) and for patient body mass index 1.59 (95% CI 1.28-1.96, p < .001). The technical failure rate for operators at proficiency level was 5% (2/40) compared with 28% (17/59) for those at the basic level (p = .003). The proficiency level group had a technical failure rate of 4% (1/26) for FST and 7% (1/14) for Prostar, p = 1.00, while corresponding rates for the basic level group were 27% (6/22) for FST and 30% (11/37) for Prostar (p = .84). There was a significant difference in cost in favor of FST, with a median difference of €800 (95% CI 710-927, p < .001). CONCLUSIONS: In aortic endovascular repair FST is a faster and cheaper technique than the Prostar technique.

Cloxacillin concentrations in serum, subcutaneous fat, and muscle in patients with chronic critical limb ischemia.

BACKGROUND: Patients suffering from critical limb ischemia (CLI) have poor wound healing in the ankle and foot areas. Secondary wound infections are frequent and often treated with prolonged courses of antibiotics. PURPOSE: This study set out to investigate to what extent the unbound fraction of 4 g of cloxacillin i.v. reaches its target organ in poorly vascularized tissues, i.e., the calf and foot of patients suffering from CLI. METHODS: Cloxacillin concentrations were measured by HPLC in serum and in microdialysis samples from skin and muscle of the lower part of the calf and as reference subcutaneously at the pectoral level in eight patients suffering from CLI (four males, four females, mean age 78 years, range 66-85 years) and in three healthy controls (two females, one male, mean age 67, range 66-68 years). RESULTS: In patients suffering from CLI, the tissue penetration of cloxacillin after a single 4 g dose was comparable to that of healthy controls, despite impaired blood circulation. CONCLUSIONS: The reduced blood flow in the peripheral vessels of the CLI patients presented here apparently is not the rate-limiting factor for delivery or tissue penetration of cloxacillin.

Abdominal hypertension and decompression: the effect on peritoneal metabolism in an experimental porcine study.

OBJECTIVE: The aim of this study was to investigate the abdominal metabolic response and circulatory changes after decompression of intra-abdominal hypertension in a porcine model. METHODS: This was an experimental study with controls. Three-month-old domestic pigs of both sexes were anesthetized and ventilated. Nine animals had a pneumoperitoneum-induced IAH of 30 mmHg for 6 hours. Twelve animals had the same IAH for 4 hours followed by decompression, and were monitored for another 2 hours. Hemodynamics, including laser Doppler-measured mucosal blood flow, urine output, and arterial blood samples were analyzed every hour along with glucose, glycerol, lactate and pyruvate concentrations, and lactate-pyruvate (l/p) ratio, measured by microdialysis. RESULTS: Laser Doppler-measured mucosal blood flow and urine output decreased with the induction of IAH and showed a statistically significant resolution after decompression. Both groups developed distinct metabolic changes intraperitoneally on induction of IAH, including an increased l/p ratio, as signs of organ hypoperfusion. In the decompression group the intraperitoneal l/p ratio normalized during the second decompression hour, indicating partially restored perfusion. CONCLUSION: Decompression after 4 hours of IAH results in an improved intestinal blood flow and a normalized intraperitoneal l/p ratio.

Intra-peritoneal microdialysis and intra-abdominal pressure after endovascular repair of ruptured aortic aneurysms.

OBJECTIVES: This study aims to evaluate intra-peritoneal (ip) microdialysis after endovascular aortic repair (EVAR) of ruptured abdominal aortic aneurysm (rAAA) in patients developing intra-abdominal hypertension (IAH), requiring abdominal decompression. DESIGN: Prospective study. MATERIAL AND METHODS: A total of 16 patients with rAAA treated with an emergency EVAR were followed up hourly for intra-abdominal pressure (IAP), urine production and ip lactate, pyruvate, glycerol and glucose by microdialysis, analysed only at the end of the study. Abdominal decompression was performed on clinical criteria, and decompressed (D) and non-decompressed (ND) patients were compared. RESULTS: The ip lactate/pyruvate (l/p) ratio was higher in the D group than in the ND group during the first five postoperative hours (mean 20 vs. 12), p = 0.005 and at 1 h prior to decompression compared to the fifth hour in the ND group (24 vs. 13), p = 0.016. Glycerol levels were higher in the D group during the first postoperative hours (mean 274.6 vs. 121.7 µM), p = 0.022. The IAP was higher only at 1 h prior to decompression in the D group compared to the ND group at the fifth hour (mean 19 vs. 14 mmHg). CONCLUSIONS: Ip l/p ratio and glycerol levels are elevated immediately postoperatively in patients developing IAH leading to organ failure and subsequent abdominal decompression.

Complete replacement of open repair for ruptured abdominal aortic aneurysms by endovascular aneurysm repair: a two-center 14-year experience.

OBJECTIVE: To present the combined 14-year experience of 2 university centers performing endovascular aneurysm repair (EVAR) on 100% of noninfected ruptured abdominal aortic aneurysms (RAAA) over the last 32 months. BACKGROUND: Endovascular aneurysm repair for RAAA feasibility is reported to be 20% to 50%, and EVAR for RAAA has been reported to have better outcomes than open repair. METHODS: We retrospectively analyzed prospectively gathered data on 473 consecutive RAAA patients (Zurich, 295; Örebro, 178) from January 1, 1998, to December 31, 2011, treated by an "EVAR-whenever-possible" approach until April 2009 (EVAR/OPEN period) and thereafter according to a "100% EVAR" approach (EVAR-ONLY period).Straightforward cases were treated by standard EVAR. More complex RAAA were managed during EVAR-ONLY with adjunctive procedures in 17 of 70 patients (24%): chimney, 3; open iliac debranching, 1; coiling, 8; onyx, 3; and chimney plus onyx, 2. RESULTS: Since May 2009, all RAAA but one have been treated by EVAR (Zurich, 31; Örebro, 39); 30-day mortality for EVAR-ONLY was 24% (17 of 70). Total cohort mortality (including medically treated patients) for EVAR/OPEN was 32.8% (131 of 400) compared with 27.4% (20 of 73) for EVAR-ONLY (P = 0.376). During EVAR/OPEN, 10% (39 of 400) of patients were treated medically compared with 4% (3 of 73) of patients during EVAR-ONLY. In EVAR/OPEN, open repair showed a statistically significant association with 30-day mortality (adjusted odds ratio [OR] = 3.3; 95% confidence interval [CI], 1.4-7.5; P = 0.004). For patients with no abdominal decompression, there was a higher mortality with open repair than EVAR (adjusted OR = 5.6; 95% CI, 1.9-16.7). In patients with abdominal decompression by laparotomy, there was no difference in mortality (adjusted OR = 1.1; 95% CI, 0.3-3.7). CONCLUSIONS: The "EVAR-ONLY" approach has allowed EVAR treatment of nearly all incoming RAAA with low mortality and turndown rates. Although the observed association of a higher EVAR mortality with abdominal decompression needs further study, our results support superiority and more widespread adoption of EVAR for the treatment of RAAA.

Adverse events during treatment of critical limb ischemia with autologous peripheral blood mononuclear cell implant.

AIM: Trials have reported clinical improvement and reduced need for amputation in critical limb ischemia (CLI) patients receiving therapeutic angiogenesis with stem cells. Our objective was to test peripheral stem cell therapy efficacy and safety to gain experiences for further work. METHODS: We included nine CLI patients (mean age 76.7 ±9.7). Stem cells were mobilized to the peripheral blood by administration of G-CSF (Filgrastim) for 4 days, and were collected on day five, when 30 mL of a stem cell suspension was injected into 40 points of the limb. The clinical efficacy was evaluated by assessing pain relief, wound healing and changes in ankle-brachial pressure index (ABI). Local metabolic and inflammatory changes were measured with microdialysis, growth factors and cytokine level determination. Patients were followed for 24 weeks. RESULTS: Four patients experienced some degree of improvement with pain relief and/or improved wound healing and ABI increase. One patient was lost to follow up due to chronic psychiatric illness; one was amputated after two weeks. Two patients had a myocardial infarction (MI), one died. One patient died from a massive mesenteric thrombosis after two weeks and one died from heart failure at week 11. Improved patients showed variable effects in cytokine-, growth factor- and local metabolic response. CONCLUSION: Even with some improvement in four patients, severe complications in four out of nine patients, and two in relation to the bone marrow stimulation, made us terminate the study prematurely. We conclude that with the increased risk and the reduced potential of the treatment, peripheral blood stem cell treatment in the older age group is less appropriate. Metabolic and inflammatory response may be of value to gain insight into mechanisms and possibly to evaluate effects of therapeutic angiogenesis.

Insights on the role of diabetes and geographic variation in patients with critical limb ischaemia.

BACKGROUND: Patients with critical limb ischaemia (CLI) unsuitable for revascularisation have a high rate of amputation and mortality (30% and 25% at 1 year, respectively). Localised gene therapy using plasmid DNA encoding acidic fibroblast growth factor (NV1FGF, riferminogene pecaplasmid) has showed an increased amputation-free survival in a phase II trial. This article provides the rationale, design and baseline characteristics of CLI patients enrolled in the pivotal phase III trial (EFC6145/TAMARIS). METHODS: An international, double-blind, placebo-controlled, randomised study composed of 525 CLI patients recruited from 170 sites worldwide who were unsuitable for revascularisation and had non-healing skin lesions was carried out to evaluate the potential benefit of repeated intramuscular administration of NV1FGF. Randomisation was stratified by country and by diabetic status. RESULTS: The mean age of the study cohort was 70 ± 10 years, and included 70% males and 53% diabetic patients. Fifty-four percent of the patients had previous lower-extremity revascularisation and 22% had previous minor amputation of the index leg. In 94% of the patients, the index leg had distal occlusive disease affecting arteries below the knee. Statins were prescribed for 54% of the patients, and anti-platelet drugs for 80%. Variation in region of origin resulted in only minor demographic imbalance. Similarly, while diabetic status was associated with a frequent history of coronary artery disease, it had little impact on limb haemodynamics and vascular lesions. CONCLUSIONS: Clinical characteristics and vascular anatomy of CLI patients with ischaemic skin lesions who were unsuitable for revascularisation therapy show little variations by region of origin and diabetic status. The findings from this large CLI cohort will contribute to our understanding of this disease process. This study is registered with ClinicalTrials.gov, number NCT00566657.

Results of the randomized, placebo-controlled clopidogrel and acetylsalicylic acid in bypass surgery for peripheral arterial disease (CASPAR) trial.

OBJECTIVE: Dual antiplatelet therapy with clopidogrel plus acetylsalicylic acid (ASA) is superior to ASA alone in patients with acute coronary syndromes and in those undergoing percutaneous coronary intervention. We sought to determine whether clopidogrel plus ASA conferred benefit on limb outcomes over ASA alone in patients undergoing below-knee bypass grafting. METHODS: Patients undergoing unilateral, below-knee bypass graft for atherosclerotic peripheral arterial disease (PAD) were enrolled 2 to 4 days after surgery and were randomly assigned to clopidogrel 75 mg/day plus ASA 75 to 100 mg/day or placebo plus ASA 75 to 100 mg/day for 6 to 24 months. The primary efficacy endpoint was a composite of index-graft occlusion or revascularization, above-ankle amputation of the affected limb, or death. The primary safety endpoint was severe bleeding (Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries [GUSTO] classification). RESULTS: In the overall population, the primary endpoint occurred in 149 of 425 patients in the clopidogrel group vs 151 of 426 patients in the placebo (plus ASA) group (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.78-1.23). In a prespecified subgroup analysis, the primary endpoint was significantly reduced by clopidogrel in prosthetic graft patients (HR, 0.65; 95% CI, 0.45-0.95; P = .025) but not in venous graft patients (HR, 1.25; 95% CI, 0.94-1.67, not significant [NS]). A significant statistical interaction between treatment effect and graft type was observed (P(interaction) = .008). Although total bleeds were more frequent with clopidogrel, there was no significant difference between the rates of severe bleeding in the clopidogrel and placebo (plus ASA) groups (2.1% vs 1.2%). CONCLUSION: The combination of clopidogrel plus ASA did not improve limb or systemic outcomes in the overall population of PAD patients requiring below-knee bypass grafting. Subgroup analysis suggests that clopidogrel plus ASA confers benefit in patients receiving prosthetic grafts without significantly increasing major bleeding risk.

High MAPK p38 activity and low level of IL-10 in intermittent claudication as opposed to stable angina.

AIM: The aim of the present pilot study was to relate the activity of MAPK p38 with the levels of pro- and anti-inflammatory cytokines in a small cohort of patients with either stable angina (N=5) or intermittent claudication (N=5) compared to healthy controls (N=10). METHODS: The activity of MAPK p38 was determined in peripheral blood mononuclear cells, isolated from whole blood by western blot using phospho-specific anti-MAPK p38 antibodies. Cytokine levels of 11 pro- and anti-inflammatory cytokines were determined from the serum using flow cytometry. RESULTS: We found a significant elevation of the MAPK p38 activity in the intermittent claudication group (P=0.0027) compared with the healthy control group whereas the stable angina group showed similar MAPK p38 activity as the healthy control group. The IL-10 level in serum found in the stable angina group was significantly higher compared with both the healthy control group (P=0.0116) and the intermittent claudication group (P=0.0317). CONCLUSION: Our results imply that there is a casual relationship between increased levels of the anti-inflammatory cytokines IL-10 and IL-4 and the activity of the MAPK p38. Possibly has IL-10 a protective role that down-regulates the activity of MAPK p38 and thereby further inflammatory processes in stable angina patients.

The next 10 years in the management of peripheral artery disease: perspectives from the 'PAD 2009' Conference.

OBJECTIVES: To briefly inform on the conclusions from a conference on the next 10 years in the management of peripheral artery disease (PAD). DESIGN OF THE CONFERENCE: International participation, invited presentations and open discussion were based on the following issues: Why is PAD under-recognised? Health economic impact of PAD; funding of PAD research; changes of treatment options? Aspects on clinical trials and regulatory views; and the role of guidelines. RESULTS AND CONCLUSIONS: A relative lack of knowledge about cardiovascular risk and optimal management of PAD patients exists not only among the public, but also in parts of the health-care system. Specialists are required to act for improved information. More specific PAD research is needed for risk management and to apply the best possible evaluation of evidence for treatment strategies. Better strategies for funding are required based on, for example, public/private initiatives. The proportion of endovascular treatments is steadily increasing, more frequently based on observational studies than on randomised controlled trials. The role of guidelines is therefore important to guide the profession in the assessment of most relevant treatment.

ESVS guidelines. Invasive treatment for carotid stenosis: indications, techniques.

The European Society for Vascular Surgery brought together a group of experts in the field of carotid artery disease to produce updated guidelines for the invasive treatment of carotid disease. The recommendations were rated according to the level of evidence. Carotid endarterectomy (CEA) is recommended in symptomatic patients with >50% stenosis if the perioperative stroke/death rate is <6% [A], preferably within 2 weeks of the patient's last symptoms [A]. CEA is also recommended in asymptomatic men <75 years old with 70-99% stenosis if the perioperative stroke/death risk is <3% [A]. The benefit from CEA in asymptomatic women is significantly less than in men [A]. CEA should therefore be considered only in younger, fit women [A]. Carotid patch angioplasty is preferable to primary closure [A]. Aspirin at a dose of 75-325 mg daily and statins should be given before, during and following CEA. [A] Carotid artery stenting (CAS) should be performed only in high-risk for CEA patients, in high-volume centres with documented low peri-operative stroke and death rates or inside a randomized controlled trial [C]. CAS should be performed under dual antiplatelet treatment with aspirin and clopidogrel [A]. Carotid protection devices are probably of benefit [C].

Impact of peripheral arterial disease in patients with diabetes--results from PROactive (PROactive 11).

We compared cardiovascular disease outcomes according to the presence of peripheral arterial disease (PAD) at baseline in a post hoc analysis from the PROactive study. Of the 5238 patients in PROactive (a study of pioglitazone versus placebo in patients with type 2 diabetes and macrovascular disease; mean follow-up=34.5 months), 1274 had PAD at baseline (619=pioglitazone; 655=placebo). Patients with PAD at baseline showed significantly higher rates of the primary endpoint, main secondary endpoint, all-cause mortality (all P<0.0001), and stroke (P=0.0175) than those with no PAD at baseline. The risk of PAD alone was similar to that of myocardial infarction alone. In patients with no PAD at baseline, the event rates of the primary endpoint (P=0.0160), main secondary endpoint (P=0.0453), and acute coronary syndrome (P=0.0287) were significantly lower with pioglitazone than with placebo. This beneficial effect of pioglitazone was not seen in patients with PAD at baseline. In the total population, there was a higher frequency of leg revascularizations with pioglitazone than placebo-this was wholly due to first events that occurred within the initial 12 months of treatment. The presence of PAD increased the risk of all major cardiovascular events. Those without PAD at baseline seemed to benefit more from pioglitazone treatment than the overall PROactive population.

Endovascular repair of the ruptured abdominal aortic aneurysm.

The present knowledge on endovascular repair of ruptured abdominal aortic aneurysms (rAAA) prevents firm conclusions when to use this method in comparison to open repair. This review article briefly summarizes results from case series, and discusses how to achieve reliable information despite the absence of randomized controlled trials. At present a careful conclusion might be that dedicated centers with an adequate organization and reasonably high volume of abdominal aortic aneurysm (AAA) should use detailed registry protocols to achieve experience and data to create an as reliable basis as possible for future recommendations.