Medical therapy for critical limb ischemia and the diabetic foot: an update.

Critical limb ischemia is the most severe manifestation of chronic peripheral artery disease (PAD). The goal of medical care is to provide symptomatic relief in patients who are unsuitable for percutaneous or surgical revascularization and to reduce systemic cardiovascular risk. PAD is a common manifestation of systemic atherosclerosis and is associated with significant morbidity and mortality. PAD represents a marker for premature cardiovascular events. Patients with PAD, even in the absence of a history of myocardial infarction or ischemic stroke, have approximately the same relative risk of death from cardiovascular causes as do patients with a history of coronary or cerebrovascular disease alone. The PARTNERS study demonstrated that patients with PAD were less likely to receive appropriate treatment for their atherosclerotic risk factors than those who were being treated for coronary artery disease. The long term prognosis of patients with PAD is significantly worse than for patients with coronary artery disease alone. Newer therapies are being investigated to treat patients with critical limb ischemia who are unsuitable candidates for revascularization, and these will be discussed briefly.

Mannheim carotid intima-media thickness and plaque consensus (2004-2006-2011). An update on behalf of the advisory board of the 3rd, 4th and 5th watching the risk symposia, at the 13th, 15th and 20th European Stroke Conferences, Mannheim, Germany, 2004, Brussels, Belgium, 2006, and Hamburg, Germany, 2011.

Intima-media thickness (IMT) provides a surrogate end point of cardiovascular outcomes in clinical trials evaluating the efficacy of cardiovascular risk factor modification. Carotid artery plaque further adds to the cardiovascular risk assessment. It is defined as a focal structure that encroaches into the arterial lumen of at least 0.5 mm or 50% of the surrounding IMT value or demonstrates a thickness >1.5 mm as measured from the media-adventitia interface to the intima-lumen interface. The scientific basis for use of IMT in clinical trials and practice includes ultrasound physics, technical and disease-related principles as well as best practice on the performance, interpretation and documentation of study results. Comparison of IMT results obtained from epidemiological and interventional studies around the world relies on harmonization on approaches to carotid image acquisition and analysis. This updated consensus document delineates further criteria to distinguish early atherosclerotic plaque formation from thickening of IMT. Standardized methods will foster homogenous data collection and analysis, improve the power of randomized clinical trials incorporating IMT and plaque measurements and facilitate the merging of large databases for meta-analyses. IMT results are applied to individual patients as an integrated assessment of cardiovascular risk factors. However, this document recommends against serial monitoring in individual patients.

Adenosine elicits an eNOS-independent reduction in arterial blood pressure in conscious mice that involves adenosine A2A receptors.

AIMS: Adenosine plays an important role in the regulation of heart rate (HR) and vascular reactivity. However, the mechanisms underlying the acute effect of adenosine on arterial blood pressure in conscious mice are unclear. Therefore, this study investigated the effect of the nucleoside on mean arterial blood pressure (MAP) and HR in conscious mice. METHODS: Chronic indwelling catheters were placed in C57Bl/6J (WT) and endothelial nitric oxide synthase knockout (eNOS(-/-)) mice for continuous measurements of MAP and HR. Using PCR and myograph analysis, involvement of adenosine receptors was investigated in human and mouse renal blood vessels. RESULTS: Bolus infusion of 0.5 mg kg(-1) adenosine elicited significant transient decreases in MAP (99.3 ± 2.3 to 70.4 ± 4.5 mmHg) and HR (603.2 ± 18.3 to 364.3 ± 49.2 min(-1)), which were inhibited by the A(2A) receptor antagonist ZM 241385. Activation of adenosine A(2A) receptors with CGS 21680 (0.02 mg kg(-1)) caused a significant reduction in MAP from 99.6 ± 1.2 to 73.1 ± 3.6 mmHg accompanied by tachycardia (610.5 ± 9.3 to 677.5 ± 9.5 min(-1)). The reduction in MAP observed after adenosine or CGS 21680 administrations was not significantly different in WT and eNOS(-/-) mice. In isolated human and mouse intrarenal arteries, adenosine caused a relaxation dependent on A(2A) adenosine receptor activation. A(2A) receptors were present in both human and mouse arteries whereas A(1) and A(2B) receptors were only present in mouse arteries. CONCLUSION: In conclusion, acute adenosine administration and selective stimulation of adenosine A(2A) receptors results in an immediate, transient eNOS-independent reduction in MAP. A(2A) receptor activation causes relaxation of human and mouse arteries.

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.

"The challenge facing renal artery revascularization: what have we not proven and why we must"?

Endovascular renal artery stent therapy for atherosclerotic renal artery stenosis (RAS) is associated with excellent acute technical success, low complication rates and acceptable long-term patency. However, the clinical benefits to patients of renal artery stenting remain uncertain. To facilitate debate regarding the treatment of RAS, we need to understand the epidemiology, basic physiology and clinical consequences of renal artery stenosis. We must attempt to determine which patients are likely to benefit from renal artery stenting, assess the nuances of the percutaneous procedure and review the current literature pertaining to renal artery stenting.

Clinical endpoints in peripheral endovascular revascularization trials: a case for standardized definitions.

BACKGROUND: Endovascular therapy is a rapidly expanding option for the treatment of patients with peripheral arterial disease (PAD), leading to a myriad of published studies reporting on various revascularization strategies. However, these reports are often difficult to interpret and compare because they do not utilize uniform clinical endpoint definitions. Moreover, few of these studies describe clinical outcomes from a patients' perspective. METHODS AND RESULTS: The DEFINE Group is a collaborative effort of an ad-hoc multidisciplinary team from various specialties involved in peripheral arterial disease therapy in Europe and the United States. DEFINE's goal was to arrive at a broad based consensus for baseline and endpoint definitions in peripheral endovascular revascularization trials for chronic lower limb ischemia. In this project, which started in 2006, the individual team members reviewed the existing pertinent literature. Following this, a series of telephone conferences and face-to-face meetings were held to agree upon definitions. Input was also obtained from regulatory (United States Food and Drug Administration) and industry (device manufacturers with an interest in peripheral endovascular revascularization) stakeholders, respectively. The efforts resulted in the current document containing proposed baseline and endpoint definitions in chronic lower limb PAD. Although the consensus has inevitably included certain arbitrary choices and compromises, adherence to these proposed standard definitions would provide consistency across future trials, thereby facilitating evaluation of clinical effectiveness and safety of various endovascular revascularization techniques. CONCLUSION: This current document is based on a broad based consensus involving relevant stakeholders from the medical community, industry and regulatory bodies. It is proposed that the consensus document may have value for study design of future clinical trials in chronic lower limb ischemia as well as for regulatory purposes.

Mannheim carotid intima-media thickness consensus (2004-2006). An update on behalf of the Advisory Board of the 3rd and 4th Watching the Risk Symposium, 13th and 15th European Stroke Conferences, Mannheim, Germany, 2004, and Brussels, Belgium, 2006.

Intima-media thickness (IMT) is increasingly used as a surrogate end point of vascular outcomes in clinical trials aimed at determining the success of interventions that lower risk factors for atherosclerosis and associated diseases (stroke, myocardial infarction and peripheral artery diseases). The necessity to promote further criteria to distinguish early atherosclerotic plaque formation from thickening of IMT and to standardize IMT measurements is expressed through this updated consensus. Plaque is defined as a focal structure that encroaches into the arterial lumen of at least 0.5 mm or 50% of the surrounding IMT value or demonstrates a thickness >1.5 mm as measured from the media-adventitia interface to the intima-lumen interface. Standard use of IMT measurements is based on physics, technical and disease-related principles as well as agreements on how to perform, interpret and document study results. Harmonization of carotid image acquisition and analysis is needed for the comparison of the IMT results obtained from epidemiological and interventional studies around the world. The consensus concludes that there is no need to 'treat IMT values' nor to monitor IMT values in individual patients apart from exceptions named, which emphasize that inside randomized clinical trials should be performed. Although IMT has been suggested to represent an important risk marker, according to the current evidence it does not fulfill the characteristics of an accepted risk factor. Standardized methods recommended in this consensus statement will foster homogenous data collection and analysis. This will help to improve the power of randomized clinical trials incorporating IMT measurements and to facilitate the merging of large databases for meta-analyses.

The safety and efficacy of the StarClose Vascular Closure System: the ultrasound substudy of the CLIP study.

BACKGROUND: The StarClose Vascular Closure System (Abbott Vascular, Redwood City, CA) features a nitinol clip that is designed to achieve closure of the femoral arteriotomy access site. The CLIP Study was performed to assess the safety and efficacy of StarClose when compared with standard manual compression following 5-6 French diagnostic or interventional percutaneous procedures. A substudy of this trial was designed to assess the utility of duplex ultrasonography to assess patency of the femoral artery and to determine access site complications (pseudoaneurysm, arteriovenous fistula, hematoma, deep vein thrombosis) in a multicenter prospective trial. This is the report of the duplex ultrasound (DUS) substudy of the CLIP trial. METHODS: A total of 17 U.S. sites enrolled 596 subjects with 483 subjects randomized at a 2:1 ratio to receive StarClose or manual compression of the arteriotomy after a percutaneous procedure. The study included roll-in (n = 113), diagnostic (n = 208), and interventional (n = 275) arms with a primary safety endpoint of major vascular complications through 30 days and a primary efficacy endpoint of postprocedure time to hemostasis. A substudy of the CLIP interventional arm evaluated DUS images of the closure site at five study sites, targeting 100 subjects at day 30 following hemostasis. The DUS protocol was devised and implemented by an independent vascular ultrasound core laboratory with extensive experience in vascular device trials. DUS inguinal region from 6 cm proximal to 6 cm distal to the arteriotomy puncture was performed. A qualitative examination was performed to determine the presence of iatrogenic vascular injuries: hematoma, pseudoaneurysm (PSA), arteriovenous fistula (AVF), and arterial/venous thrombosis or stenosis using 2-dimensional gray scale, color, and focused Doppler images. RESULTS: DUS of 96 subjects randomized to StarClose (n = 71) and compression (n = 25) were performed and evaluated. There was no evidence of hematoma, PSA, or AVF observed in the StarClose group. No StarClose subjects in the substudy had a PSA or AVF. All patients in the substudy demonstrated patency of the access site artery and vein without thrombosis or stenosis. Finally, in the entire study cohort, no clinically-driven DUS studies demonstrated iatrogenic vascular injury or vessel thrombosis in the StarClose treated patients. CONCLUSION: DUS, a safe and reliable method for determining the safety and efficacy of access site closure devices, is a reliable, safe, inexpensive and accurate method of assessing vascular access site complications in multicenter trials. In this substudy of the CLIP study, DUS found no statistical difference in access site complications between the StarClose and manual compression groups. Both groups maintained vessel patency without stenosis, thrombosis, hematoma, pseudoaneurysm, or AV fistula.

Renal artery stent revascularization with embolic protection in patients with ischemic nephropathy.

A prospective analysis of renal artery stent revascularization with distal embolic protection in a high-risk patient population with ischemic nephropathy is presented. A total of 63 patients (median age 70.2 years, range 54-86 years) had significant atherosclerotic stenosis of 83 renal arteries documented on pre-procedural imaging. All patients had baseline chronic renal insufficiency with a documented deterioration in renal function in the 6 months before revascularization. The endovascular technique used in all patients involved primary passage of an embolic filter into the distal main renal artery followed by primary stent deployment with a balloon expandable stainless steel stent. The filter baskets were recaptured and contents submitted for pathological analysis. At 6 months post-intervention, 97% of patients demonstrated stabilization or improvement in renal function. Only 3% of patients had an inexorable decline in renal function, unchanged by the intervention. After a mean follow up of 16.0 months (6-27), 94% of patients demonstrated stabilization or improvement in renal function. One patient suffered an acute post-procedural deterioration in renal function. In total, 60% of the filter baskets contained embolic material. This study confirms the technical feasibility of renal artery stent deployment with adjuvant embolic protection. The excellent results for renal preservation at 6 months post-intervention also suggest that a distal embolic protection device may improve the impact of percutaneous renal revascularization on progressive deterioration in renal function. The postulated mechanism is through the prevention of atheromatous embolization and the embolic yield from the distal filters supports this hypothesis. Patients most likely to receive the greatest benefit are those with mild baseline chronic renal insufficiency and a recent decline in renal function.

Tibioperoneal (outflow lesion) angioplasty can be used as primary treatment in 235 patients with critical limb ischemia: five-year follow-up.

BACKGROUND: In a prospective, nonrandomized, consecutive series of tibioperoneal vessel angioplasty (TPVA), critical limb ischemia (CLI) patients' data were analyzed with regard to immediate and follow-up success. METHODS AND RESULTS: TPVA was successful in 270 of 284 critically ischemic limbs (95%), with 167 limbs (59%) requiring dilatation of 333 ipsilateral inflow obstructions to access and successfully dilate 486 of 529 (92%) tibioperoneal lesions. A clinical success (relief of rest pain or improvement of lower-extremity blood flow) was attained in 270 limbs at risk (95%). Clinical 5-year follow-up of 215 of 221 successful CLI patients (97%) with 266 successfully revascularized limbs revealed that bypass surgery occurred in 8% and significant amputations in 9% of limbs; 91% of the limbs were salvaged. The cohort's probability of survival was 56%: 58% for Fontaine class III and 33% for class IV patients. Class III compared with class IV patients had significantly (P<0.05) fewer surgical bypasses (3% versus 16%) and amputations: above-knee, 1% versus 4%; below-knee, 3% versus 12%; and transmetatarsal, <1% versus 21%. CONCLUSIONS: TPVA, often in combination with inflow lesions, is an effective primary treatment for critical limb ischemia. The poor cumulative survival reflects the existence of severe comorbidities, which could potentially be affected by aggressive and effective cardiovascular diagnostic and therapeutic strategies.

Haploinsufficiency for one COL3A1 allele of type III procollagen results in a phenotype similar to the vascular form of Ehlers-Danlos syndrome, Ehlers-Danlos syndrome type IV.

Mutations in the COL3A1 gene that encodes the chains of type III procollagen result in the vascular form of Ehlers-Danlos syndrome (EDS), EDS type IV, if they alter the sequence in the triple-helical domain. Although other fibrillar collagen-gene mutations that lead to allele instability or failure to incorporate proalpha-chains into trimers-and that thus reduce the amount of mature molecules produced-result in clinically apparent phenotypes, no such mutations have been identified in COL3A1. Furthermore, mice heterozygous for Col3a1 "null" alleles have no identified phenotype. We have now found three frameshift mutations (1832delAA, 413delC, and 555delT) that lead to premature termination codons (PTCs) in exons 27, 6, and 9, respectively, and to allele-product instability. The mRNA from each mutant allele was transcribed efficiently but rapidly degraded, presumably by the mechanisms of nonsense-mediated decay. In a fourth patient, we identified a point mutation, in the final exon, that resulted in a PTC (4294C-->T [Arg1432Ter]). In this last instance, the mRNA was stable but led to synthesis of a truncated protein that was not incorporated into mature type III procollagen molecules. In all probands, the presenting feature was vascular aneurysm or rupture. Thus, in contrast to mutations in genes that encode the dominant protein of a tissue (e.g., COL1A1 and COL2A1), in which "null" mutations result in phenotypes milder than those caused by mutations that alter protein sequence, the phenotypes produced by these mutations in COL3A1 overlap with those of the vascular form of EDS. This suggests that the major effect of many of these dominant mutations in the "minor" collagen genes may be expressed through protein deficiency rather than through incorporation of structurally altered molecules into fibrils.

Therapeutic thrombin injection of pseudoaneurysms: a multicenter experience.

The standard non-invasive treatment of pseudoaneurysms has been ultrasound-guided compression (UGC). Problems with UGC include pain at the site of compression, long compression times and incomplete closure. Each of these difficulties is exacerbated with large pseudoaneurysms. Recently, ultrasound-guided injection of pseudoaneurysms with thrombin has gained popularity. The goal of this study was to report a multicenter registry using this technique and in so doing detail the clinical utility and safety of this emerging procedure. The medical records of all patients diagnosed with pseudoaneurysm in the vascular laboratory who underwent thrombin injection over the past year were reviewed for patient characteristics and clinical outcome. There were 91 patients (55 male) with a mean age of 69 years. Three patients also had an arteriovenous fistula. The majority of patients were receiving one or more antiplatelet agents and/or anticoagulants. All patients underwent pseudoaneurysm injection with bovine thrombin. The mean aneurysm diameter was 3.3 cm, with a range of 1.5-6.3 cm. Successful thrombosis of the pseudoaneurysm was achieved in 89/91 (98%) of cases. Anticoagulation with heparin was used in one of the unsuccessful cases. In two cases, UGC was used to close a small active region that did not completely thrombose after thrombin injection. There were two patients who had recurrence of pseudoaneurysm the day after successful injection and thrombosis of the pseudoaneurysm. There were no local complications after injection; however, one patient suffered a pulmonary embolus that was thought to be unrelated to the procedure. In conclusion, thrombin injection for the treatment of pseudoaneurysms is safe and effective, even in patients receiving anticoagulation. This procedure should be considered as the initial therapeutic approach for peripheral pseudoaneurysms.

Clinical evaluation and options for infrainguinal atherosclerosis therapy: when to intervene?

Cardiologists have gained considerable experience and expertise in the diagnosis and management of coronary artery disease. Interventional therapy has now become a standard cornerstone of therapy for coronary artery disease, and endoluminal stents are being used in over 70% of all coronary interventions. Diagnosis and treatment of peripheral arterial disease (PAD) has recently gained momentum. In the past, vascular surgeons and interventional radiologists were the classic caregivers for PAD patients, with an interest in deciding between intervention or no intervention. In addition, the majority of PAD patients had few medical resources since many medical specialists did not view PAD as important for many reasons, such as: (1) few effective options for the management of patients with PAD, (2) PAD did not represent a significant health hazard to patients, (3) few patients actually suffered from PAD, and (4) patients did not view PAD as a significant limitation in their quality of life. Over the past decade, a new medical specialty, vascular medicine, had dedicated itself to the comprehensive management of these complex patients. Vascular medicine specialists are predominantly internists and cardiologists. These physicians not only view PAD as an important medical issue, they understand the increasing prevalence of PAD among the "baby-boomer" generation, the shortened life-expectancy of patients with PAD, and the marked reduction in the quality of life among PAD patients. Most importantly, vascular medicine physicians are now aware of several effective options for patients with PAD.

Hypertension and renal artery stenosis: a complex clinical scenario.

Hypertension remains the most common reason for patients to visit physicians in the United States. Although awareness of hypertension among patients continues to increase, adequate control of hypertension remains poor. In addition, as the population of patients with hypertension ages, atherosclerosis becomes increasingly prevalent. Atherosclerotic renal artery stenosis is the most common secondary cause of hypertension and can cause hypertension to be difficult to control. Atherosclerotic renal artery stenosis may also result in chronic renal insufficiency. The physician must be aware of the clinical scenarios in which renal artery stenosis may occur, methods of diagnosis, and indications for intervention.

Carotid artery disease: natural history, diagnosis, and therapy.

Stroke remains a major complication of atherosclerotic cerebrovascular disease, with extracranial carotid occlusive disease accounting for nearly one-third of all events. Although historical symptoms and physical examination findings are important, objective testing with carotid duplex ultrasonography and magnetic resonance arteriography represent the foundation for therapeutic decision making. Contrast arteriography is playing a decreasing role in the evaluation of patients with carotid artery disease. Options for therapy, based on the presence or absence of symptoms and degree of stenosis, include antiplatelet therapy with cardiovascular risk factor modification, carotid endarterectomy, and more recently, endovascular therapy.

Intra-arterial reteplase for the treatment of acute limb ischemia.

The removal of urokinase from the market has created a dilemma for interventionists and vascular surgeons treating patients with acute limb threatening ischemia due to arterial thrombosis or embolization. Reteplase is a newer, fibrin-specific thrombolytic agent with properties that make it an attractive alternative to urokinase. We report two cases of successful treatment of acute, limb threatening ischemia with intra-arterial Reteplase therapy.