Rationale and design for the study of rivaroxaban to reduce thrombotic events, hospitalization and death in outpatients with COVID-19: The PREVENT-HD study.

BACKGROUND: COVID-19 is associated with both venous and arterial thrombotic complications. While prophylactic anticoagulation is now widely recommended for hospitalized patients with COVID-19, the effectiveness and safety of thromboprophylaxis in outpatients with COVID-19 has not been established. STUDY DESIGN: PREVENT-HD is a double-blind, placebo-controlled, pragmatic, event-driven phase 3 trial to evaluate the efficacy and safety of rivaroxaban in symptomatic outpatients with laboratory-confirmed COVID-19 at risk for thrombotic events, hospitalization, and death. Several challenges posed by the pandemic have necessitated innovative approaches to clinical trial design, start-up, and conduct. Participants are randomized in a 1:1 ratio, stratified by time from COVID-19 confirmation, to either rivaroxaban 10 mg once daily or placebo for 35 days. The primary efficacy end point is a composite of symptomatic venous thromboembolism, myocardial infarction, ischemic stroke, acute limb ischemia, non-central nervous system systemic embolization, all-cause hospitalization, and all-cause mortality. The primary safety end point is fatal and critical site bleeding according to the International Society on Thrombosis and Haemostasis definition. Enrollment began in August 2020 and is expected to enroll approximately 4,000 participants to yield the required number of end point events. CONCLUSIONS: PREVENT-HD is a pragmatic trial evaluating the efficacy and safety of the direct oral anticoagulant rivaroxaban in the outpatient setting to reduce major venous and arterial thrombotic events, hospitalization, and mortality associated with COVID-19.

Five-Year Management of Vascular Injuries of the Extremities in the "Real-World" Setting in Northeastern Greece: The Role of Iatrogenic Traumas.

BACKGROUND: Vascular trauma comprises a diagnostic and surgical challenge. Aim of this study was to present the vascular traumas treated in our Tertiary Hospital during the last 5 years. METHODS: We retrospectively reviewed the surgical records of our vascular department and documented the site and type of vascular injuries of the extremities along with the concurrence of musculoskeletal injuries. The type and outcome of surgical interventions were also recorded. RESULTS: Fifty-eight cases of vascular trauma were recorded (39 in the upper and 19 in the lower extremities). Overall, iatrogenic traumas accounted for 41.3% of cases. The arterial injuries of the upper limb were blunt and penetrating in 27% and 67%, respectively. The most affected artery in the upper limb was the radial artery (37.8%), followed by the ulnar artery (27%) and the brachial artery (24.3%). Orthopedic injuries were recorded in 19% of patients. Management involved simple revascularization, bypass operations, patch arterioplasty and endovascular management in 48.7%, 33.3%, 5.1%, and 5.1%, respectively. The most affected site in the lower extremity was the common femoral artery (36.8%) followed by the popliteal artery (21%). Bone fractures were reported in 5 cases (26.3%). The surgical management involved bypass, simple revascularization, patch arterioplasty in 42.1%, 26.3%, and 21%, respectively. Endovascular management was performed in 10.5%. CONCLUSIONS: A considerable percentage of iatrogenic vascular injuries was recorded, affecting both the upper and lower limbs. Despite the trend toward centralization of vascular services, a basic service of vascular surgery should be available in most sites to ensure that patients with vascular injuries receive fast and appropriate care.

Isolated limb perfusion for soft tissue sarcoma: Current practices and future directions. A survey of experts and a review of literature.

Soft tissue sarcomas constitute 1% of adult malignant tumors. They are a heterogeneous group of more than 50 different histologic types. Isolated limb perfusion is an established treatment strategy for locally advanced sarcomas. Since its adoption for sarcomas in 1992, after the addition of TNFα, few modifications have been done and although indications for the procedure are essentially the same across centers, technical details vary widely. The procedures mainly involves a 60 min perfusion with melphalan and TNFα under mild hyperthermia, achieving a limb preservation rate of 72-96%; with an overall response rates from 72 to 82.5% and an acceptable toxicity according to the Wieberdink scale. The local failure rate is 27% after a median follow up of 14-31 months compared to 40% of distant recurrences after a follow up of 12-22 months. Currently there is no consensus regarding the benefit of ILP per histotype, and the value of addition of radiotherapy or systemic treatment. Further developments towards individualized treatments will provide a better understanding of the population that can derive maximum benefit of ILP with the least morbidity.

Electroacupuncture Attenuates Limb Ischemia-Reperfusion-Induced Lung Injury Via p38 Mitogen-Activated Protein Kinase-Nuclear Factor Erythroid-2-Related Factor-2/Heme Oxygenase Pathway.

BACKGROUND: Electroacupuncture has been reported to protect the body from organ damages, but its mechanisms remain to be explored. This research was designed to investigate the function of electroacupuncture in lung injury resulted from hind limb ischemia-reperfusion (LIR) and whether p38 mitogen-activated protein kinase (p38 MAPK)-mediated nuclear factor erythroid-2-related factor-2 (Nrf2)/heme oxygenase (HO)-1 pathway contributes to the protective effect of electroacupuncture on LIR-originated lung damage. MATERIALS AND METHODS: Rabbits were subjected to occluding femoral artery for 2 h. Then they received reperfusion for 4 h to establish lung injury model. Electroacupuncture stimulation was performed bilaterally at Feishu and Zusanli acupoints for 15 min once a day for 5 d before the experiment and throughout the hind LIR model performing in the experimental day. Blood samples and lung tissues were collected to examine the role of electroacupuncture treatment in inflammatory response, oxidative stress, and lung injury. Both the protein expression and the messenger RNA level of Nrf2 and HO-1 were detected. RESULTS: The results showed that electroacupuncture treatment remarkably alleviated lung injury, decreased inflammatory cytokines secretion, attenuated lung oxidative stress, increased the amount of Nrf2 and HO-1, and increased the ratio of phospho-p38 MAPK to p38 MAPK after LIR. However, the protective effects exerted by electroacupuncture were reversed to some extent by the preconditioning with SB203580, a p38 MAPK-specific inhibitor. CONCLUSIONS: These results suggested that electroacupuncture could attenuate lung injury in rabbits subjected to LIR by inhibition of proinflammatory cytokine response and oxidative stress through activating p38 MAPK-mediated Nrf2/HO-1 pathway.

Classificação WifI: o novo sistema de classificação da Society for Vascular Surgery para membros inferiores ameaçados, uma revisão de literatura / WIfI classification: the Society for Vascular Surgery lower extremity threatened limb classification system, a literature review

Resumo A Society for Vascular Surgery propôs nova classificação para o membro inferior ameaçado, baseada nos três principais fatores influenciadores do risco de amputação do membro: ferida (Wound, W), isquemia (Ischemia, I) e infecção do pé (foot Infection, fI): a classificação WIfI. Esta abrange também os diabéticos, anteriormente excluídos do conceito de isquemia crítica do membro devido a seu quadro clínico complexo. O objetivo da classificação era fornecer estratificação de risco precisa e precoce ao paciente com membro inferior ameaçado; auxiliar no manejo clínico, permitindo comparar terapias alternativas; e predizer o risco de amputação em 1 ano e a necessidade de revascularização. O objetivo deste estudo é reunir os principais pontos abordados sobre a classificação WIfI no meio científico. A maior parte dos estudos de validação da classificação demonstram sua associação à predição de salvamento do membro, eventos de reintervenção, amputação e estenose, taxas de amputação maior e menor, sobrevida livre de amputação, e cicatrização de feridas.

Abstract The Society for Vascular Surgery has proposed a new classification system for the threatened lower limb, based on the three main factors that have an impact on limb amputation risk: Wound (W), Ischemia (I) and foot Infection ("fI") - the WIfI classification. The system also covers diabetic patients, previously excluded from the concept of critical limb ischemia because of their complex clinical condition. The classification's purpose is to provide accurate and early risk stratification for patients with threatened lower limbs; assisting with clinical management, enabling comparison of alternative therapies; and predicting risk of amputation at 1 year and the need for limb revascularization. The objective of this study is to collect together the main points about the WIfI classification that have been discussed in the scientific literature. Most of the studies conducted for validation of this classification system prove its association with factors related to limb salvage, such as amputation rates, amputation-free survival, prediction of reintervention, amputation, and stenosis (RAS) events, and wound healing.

A Qualitative Study Exploring Patient Concerns and Values in Chronic Limb-Threatening Ischemia.

BACKGROUND: Chronic limb-threatening ischemia (CLTI) is the debilitating end stage of peripheral artery disease, causing patients to experience low quality of life and poor health outcomes. It is unknown which aspects of care patients with CLTI value. This pilot qualitative study aims to explore patients' concerns and values related to CLTI treatment, to better inform patient-centered care. METHODS: A qualitative study design was piloted to explore the experiences of patients with CLTI undergoing elective vascular surgery. In-depth, semistructured interviews were recorded preoperatively and 3 mo after discharge. Transcribed interviews were analyzed using content analysis, to derive patient-centered themes. Findings were mapped to a framework of patient-centered care. RESULTS: Twelve interviews from six participants were analyzed. Five themes related to participant experiences of CLTI were identified: treatment and diagnosis, concerns about symptoms, limitations in physical function, social function, and emotional function. Participants expressed how CLTI intruded on all aspects of their lives. Framework analysis demonstrated CLTI patients valued patient-centered care relating to both relational and functional aspects of care. In particular, participants valued supportive and trustworthy care, in addition to integrated, holistic care that recognized the patient in the context of their overall health and life. CONCLUSIONS: Feasibility was demonstrated for both study design and methodology. Data obtained from interviews were sufficiently "rich and thick" in quality and quantity to allow for common themes related to experience and health care values in patients with CLTI to be identified. If confirmed in future studies, these findings will enhance patient-centered care in CLTI.

[Efferent methods and hyperbaric oxygen therapy for great vessels injuries of extremities]. / Rezul'taty primeneniia éfferentnykh metodov i giperbaricheskoi oksigenatsii pri travmakh krupnykh arterii konechnostei.

AIM: To evaluate an efficacy of efferent therapy of great vessels injuries of extremities and acute limb ischemia. MATERIAL AND METHODS: There were 197 patients (main group -107, control group - 90 patients) with great vessels injuries of extremities and acute limb ischemia. The patients of the main group underwent plasmapheresis, ultraviolet irradiation of blood (UVIB) and hyperbaric oxygen (HBO) therapy. Efferent methods were used depending on the severity of acute ischemia, intoxication and infection (intoxication - plasmapheresis, ischemia - plasmapheresis + HBO, infections - UVIB, their combination - plasmapheresis + UVIB + HBO). RESULTS: Limb amputation and necrectomy were required only in 2 (1.96%) and 3 (2.8%) patients of the main group, mortality - 0.94% (n=1). In the control group these values were 16 (17.8%), 10 (11.1%) and 7 (7.8%), respectively. CONCLUSION: Efferent methods are effective in patients with traumatic vascular injuries and acute limb ischemia regarding improvement of clinical outcomes and 2-fold reduction of hospital-stay, less number of amputations and decreased mortality rate.

Hyperbaric oxygen therapy promotes wound repair in ischemic and hyperglycemic conditions, increasing tissue perfusion and collagen deposition.

The treatment of chronic wounds remains inconsistent and empirical. Hyperbaric oxygen therapy (HBOT) is a promising method to improve wound repair but there is still a lack of understanding of its mechanisms of action and its indications are not yet clearly defined. We studied the effects of HBOT in four different wound conditions by inflicting bilateral wounds on the dorsal aspect of the feet of nonischemic or ischemic limbs in normoglycemic or hyperglycemic rats. To create an ischemic condition, arterial resection was performed unilaterally. Forty-four animals received HBOT five times a week until complete wound closure. Wound repair was compared with 44 rats receiving standard dressing only. HBOT increased blood flow and accelerated wound closure in ischemic and hyperglycemic wounds, most significantly when the two conditions were combined. Wound contraction and reepithelialization were similarly stimulated by HBOT. The acceleration of wound contraction was not associated with increased myofibroblasts expression, nor fibroblast recruitment or higher cell count in the granulation tissue. Of note, we observed a significant increase in collagen deposition in early time points in ischemic wounds receiving HBOT. This data emphasizes that an early application of HBOT might be crucial to its efficacy. We concluded that wounds where ischemia and hyperglycemia are combined, as it is often the case in diabetic patients, have the best chance to benefit from HBOT.

The Geriatric Nutritional Risk Index is Independently Associated with Prognosis in Patients with Critical Limb Ischemia Following Endovascular Therapy.

OBJECTIVES: Patients with critical limb ischemia (CLI) have poor overall and limb prognosis. Although nutritional status influences overall prognosis, and the Geriatric Nutritional Risk Index (GNRI) is a widely used, simple and well established nutritional status screening method, the association between the GNRI and the overall and limb prognosis of patients with CLI following endovascular therapy (EVT) has not been explored. METHODS: Clinical outcomes were retrospectively evaluated in 473 consecutive patients (74 ± 10 years; 59% male) with CLI who underwent EVT. The GNRI on admission was calculated as follows: [14.89 × albumin (g/dL)] + [41.7 × (body weight/ideal body weight)]. Cox proportional hazard analysis was performed to explore the independent association between the GNRI and mortality and major amputation. RESULTS: Patients (53% ambulatory, 38% wheelchair bound, and 9% bedridden) were divided into two groups based on the median GNRI: the higher group (GNRI ≥ 91.2, n = 237) and the lower group (GNRI < 91.2, n = 236). Median follow up duration after EVT was 11.3 months. Three years after EVT, the survival rate (74% in the higher GNRI, and 48% in the lower GNRI, respectively), and limb salvage rate (92% in the higher GNRI, and 84% in the lower GNRI) were significantly lower in the lower GNRI group. GNRI (hazard ratio [HR], 1.03; 95% confidence interval [CI], 1.01-1.05), along with being wheelchair bound (HR, 1.87; 95% CI 1.17-2.97; vs. ambulatory status), being bedridden (HR, 3.10; 95% CI, 1.63-2.97; vs. ambulatory status), being on hemodialysis (HR, 2.33; 95% CI, 1.49-3.64), and having chronic heart failure (HR, 2.22; 95% CI, 1.44-3.43) were the independent predictors of mortality. The GNRI (HR, 1.04; 95% CI, 1.01-1.07), being bedridden (HR, 4.15; 95% CI, 1.67-10.3; vs. ambulatory status), isolated below knee disease (HR, 2.49; 95% CI, 1.30-4.77), and hemodialysis (HR, 2.44; 95% CI, 1.23-4.85) were independently associated with major amputation. CONCLUSIONS: The GNRI on admission was independently associated with mortality and major amputation after EVT in patients with CLI.

Effect of acute inspiratory muscle exercise on blood flow of resting and exercising limbs and glucose levels in type 2 diabetes.

To evaluate the effects of inspiratory loading on blood flow of resting and exercising limbs in patients with diabetic autonomic neuropathy. Ten diabetic patients without cardiovascular autonomic neuropathy (DM), 10 patients with cardiovascular autonomic neuropathy (DM-CAN) and 10 healthy controls (C) were randomly assigned to inspiratory muscle load of 60% or 2% of maximal inspiratory pressure (PImax) for approximately 5 min, while resting calf blood flow (CBF) and exercising forearm blood flow (FBF) were measured. Reactive hyperemia was also evaluated. From the 20 diabetic patients initially allocated, 6 wore a continuous glucose monitoring system to evaluate the glucose levels during these two sessions (2%, placebo or 60%, inspiratory muscle metaboreflex). Mean age was 58 ± 8 years, and mean HbA1c, 7.8% (62 mmol/mol) (DM and DM-CAN). A PImax of 60% caused reduction of CBF in DM-CAN and DM (P<0.001), but not in C, whereas calf vascular resistance (CVR) increased in DM-CAN and DM (P<0.001), but not in C. The increase in FBF during forearm exercise was blunted during 60% of PImax in DM-CAN and DM, and augmented in C (P<0.001). Glucose levels decreased by 40 ± 18.8% (P<0.001) at 60%, but not at 2%, of PImax. A negative correlation was observed between reactive hyperemia and changes in CVR (Beta coefficient = -0.44, P = 0.034). Inspiratory muscle loading caused an exacerbation of the inspiratory muscle metaboreflex in patients with diabetes, regardless of the presence of neuropathy, but influenced by endothelial dysfunction. High-intensity exercise that recruits the diaphragm can abruptly reduce glucose levels.

[Cost and cost-effectiveness in the treatment of peripheral arterial occlusion disease - what is proven?]. / Kosten und Kosteneffizienz bei der Behandlung der peripheren arteriellen Verschlusskrankheit - was ist gesichert?

BACKGROUND: This overview comments on the health-care relevance of peripheral arterial occlusive disease (PAOD) in patients with intermittent claudication (IC) and critical limb ischaemia (CLI). We evaluated different treatment modalities in terms of cost-effectiveness. METHOD: For the literature review, the Medline database (PubMed) was searched under the key words "critical limb ischemia AND cost", "critical limb ischemia AND economy", "peripheral arterial disease AND cost", "peripheral arterial disease AND economy". RESULTS: In the years 2005 to 2009, the hospitalisations of patients with PAOD rose disproportionately in Germany by 20 %, to 483,961 hospital admissions. By comparison, hospital admissions altogether increased by only 8 %. The average in-patient costs were estimated to be approximately € 5000 per PAOD-patient - a rather conservative estimate. For the patient with IC the economic data position is clear, supervised exercise training is by far the most cost-effective treatment option, followed by percutaneous transluminal angioplasty (PTA) and finally the peripheral bypass. In accordance with the guidelines of the UK, the latter is therefore indicated only if PTA fails or is technically not possible. In patients with CLI, the situation is not obvious. Indeed, a short-term economic advantage can be calculated for the PTA, the long-term comparison of both methods, however, is impossible due to insufficient data. In addition, the risk factors for the patient have to be included in the calculation. This was indeed demonstrated in the short-term, but could not be analysed in the long-term follow-up. CONCLUSION: The issue of greater cost-effectiveness of open or endovascular treatment in patients with CLI is uncertain, the studies and patient populations are too heterogeneous. Further studies are urgently needed to structure the sequence of the various treatment options in guidelines and clinical pathways.

Effect of Mailuoning injection on 8-iso-prostaglandin F2 alpha and superoxide dismutase in rabbits with extremity ischemia-reperfusion injury.

BACKGROUND: To date, there are no effective treatments for extremity ischemia-reperfusion (IR) injury. The objective of the present study was to explore the protective effect of Mailuoning on IR injury by investigating the plasma levels of 8-iso-prostaglandin F2 alpha (8-iso-PGF2α) and the activity of superoxide dismutase (SOD) in rabbits. MATERIALS AND METHODS: The experimental models of posterior limb IR injury were established in thirty rabbits that were divided into three groups: the sham, IR, and IR + Mailuoning groups. At the end of ischemia, Mailuoning was injected intravenously into the rabbits in the IR + Mailuoning group, and normal saline solution was administered to the rabbits in the sham and IR groups. Venous blood samples were collected to measure the levels of 8-iso-PGF2α and the activity of SOD in the plasma at the following time points: at the onset of ischemia, the end of ischemia, and 2, 4, 8, 12, and 24 h after reperfusion. The skeletal muscles were harvested to examine the ultrastructure. RESULTS: The levels of 8-iso-PGF2α increased significantly and SOD activity decreased in the IR group at every time point after reperfusion (P <0.01 or P <0.05). In contrast, the levels of 8-iso-PGF2α and SOD activity were not significantly different after reperfusion in the IR + Mailuoning group (P >0.05) but were significantly different compared with the IR group (P <0.01). Using electron microscopy, the skeletal muscle injury was shown to be milder in the IR+ Mailuoning group after reperfusion compared with the IR group. CONCLUSIONS: The Mailuoning is capable of decreasing the excessive production of 8-iso-PGF2α and protecting SOD activity, thereby exhibiting a protective effect on extremity IR injury.

[Dermal and inhalation poisoning. Rare guests in our intensive care units?]. / Dermale und inhalative Intoxikationen. Seltene Gäste auf unseren Intensivstationen?

Patients with dermal and inhalation poisoning are uncommon in intensive care treatment. We describe the diagnostics and specific toxicological treatment of patients with hydrofluoric acid burns. For inhalation poisoning, we focus on smoke inhalation, especially the management of cyanide and carbon monoxide poisoning. Special attention is given to the use of hyperbaric oxygenation for the treatment of carbon monoxide poisoning.

[Traditional bonesetter's gangrene of limb in children in Regional Hospital of Kaolack (Senegal)]. / Gangrène de membre à la suite d'un traitement traditionnel de fractures par attelle en bambou chez l'enfant à l'Hôpital régional de Kaolack (Sénégal).

Little published data exist on the morbidity and mortality associated with poor trauma care in developing countries. This report highlights our experience with iatrogenic limb gangrene related to fracture management by traditional bonesetters. Children with bonesetter's gangrene were identified from a prospectively recorded paediatric surgery database at the Regional Hospital of Kaolack in Central Senegal. 21 children were treated for bonesetter's gangrene during a 18-month period (January 2007 up to June 2008). The average age was 10 years (range, 5 to 15 years). Bonesetter's gangrene was more common in boys (90.5%) and occurred almost exclusively in children from rural areas where access to health care was limited. 16 children underwent proximal extremity amputation. Complications included one case of tetanus. Bonesetter's gangrene is a preventable complication that results from a failure of child health planners to recognize the importance of basic trauma care. Management of fractures should be considered an essential component of child health programs in developing countries.

[Investigation of the essence of chilliness and cold limbs of yang deficiency syndrome in Chinese medicine based on the adaptability of body to cold stimulation].

Chinese medicine (CM) theories attach great importance to the interaction between the human body and the environment. From this entry point, based on a great number of related CM literatures and knowledge of modern medicine, this paper investigated the essence of chilliness and cold limbs of yang deficiency syndrome. The differences on cognition and solution to this problem between CM theory and modern medicine theory were also analyzed. Firstly, the close relationship between the CM concepts of yang deficiency, "external cold", and winter was put forward after a review of yang deficiency in CM scripture Huangdi Neijing. Chilliness and cold limbs of yang deficiency patients was believed to be highly similar to the body state of "external cold" of healthy people in winter. Secondly, the state of "external cold" was described as a reduction of body surface blood flow (heat) with references to the adaptability to cold stimulation. Then according to a collection of physiological and pathological factors which may cause such reduction, we proposed that the essence of chilliness and cold limbs of yang deficiency patients may probably be the state of reduction of body surface blood flow (heat) due to some pathological factors already known as heart failure, poor circulation, and thyroid dysfunction. Thirdly, by using the method of "syndrome differentiation through formula effects assessment", this recognition was confirmed because the pharmacological activities of cardiotonic or peripheral vasodilating, or surface temperature increasing were found in a great number of single medicines and prescriptions applied to yang deficiency syndrome in CM.

[The experience with thoracoscopic sympathectomy for the treatment of distal lesions of limb arteries].

The study included 107 patients with distal lesions of limb arteries treated with the use of thoracoscopic sympathectomy. The best results in the early postoperative period were obtained in patients with Raynaud's disease. Modifications introduced into the methods of its treatment permitted to retain effectiveness of sympathectomy till the late postoperative period in 90% of the patients. Surgery for obliterative endarteritis and atherosclerosis was viewed as a possibility to preserve the supporting function of the limb. This purpose was attained in 73.2 and 62.5% of the patients respectively in the early and in 62 and 25% in the late postoperative periods.

Disseminated intravascular coagulation, meningococcal infection, and ischemic changes affecting the lower extremities: a case study.

A middle-aged woman presented from an outside hospital with a diagnosis of Neisseria meningitidis and meningococcemia. A nonpalpable purpuric skin rash evolved into multiple wounds, with gradual necrosis of bilateral lower and upper extremities. Throughout the course of hospitalization, the patient developed ventricular tachycardia, normocytic anemia, thrombocytosis, Clostridium difficile infection, depression, and transient right eye blindness. The finding of decreased CH50 in the complement cascade was considered as the potential cause of the meningococcemia. The subsequent ischemia and necrosis of extremities were attributed to the systemic effect and trauma ensuing from N. meningitidis.

Impairment of human cell-based vasculogenesis in rats by hypercholesterolemia-induced endothelial dysfunction and rescue with L-arginine supplementation.

OBJECTIVE: Clinical efficacy of cardiac cell therapy may be compromised by its target population, patients with endothelial dysfunction. In vivo inhibition by endothelial dysfunction has been demonstrated for protein angiogenesis but remains unclear for cell therapy. We examined whether hypercholesterolemia inhibits vasculogenic effects of transplanted human circulating progenitor cells in ischemic tissue and whether L-arginine, a nitric oxide donor, might prevent impairment. METHODS: Athymic rats were fed either normal (group A) or high-cholesterol diets, the latter without (group B) or with (group C) oral L-arginine supplementation. Two weeks later, these rats underwent left femoral artery ligation followed by injection of 2 x 10(6) human circulating progenitor cells into left hind-limb muscle. A fourth group (group D) received supplemented high-cholesterol diets but no cells. RESULTS: Group B had biochemical evidence of endothelial dysfunction and reduced tissue endothelial nitric oxide synthase expression, whereas group A levels were the same as in group C. By 21 postoperative days, left hind-limb perfusion had recovered fully in groups A and C, partially in D, and not at all in B (38% lower than group A, P < or = .004). Lower arteriolar densities were found in groups and B and D than in groups A and C (P < or = .02). Engrafted human cell numbers were equivalent in all cell-transplanted groups after 3 weeks. CONCLUSIONS: Endothelial dysfunction inhibited effects of cell therapy, specifically vasculogenesis, suggesting a role for substrate modification to overcome this inhibition. Involved mechanisms appear related to use of cells but not engraftment and require further investigation.