Low-intensity pulsed ultrasound improves symptoms in patients with Buerger disease: a double-blinded, randomized, and placebo-controlled study.

Here we report the effects of low-intensity pulsed ultrasound (LIPUS) on symptoms in peripheral arterial disease patients with Buerger disease. A double-blinded and randomized study with active and inactive LIPUS was conducted. We assessed symptoms in leg circulation during a 24-week period of LIPUS irradiation in 12 patients with Buerger disease. Twelve patients without LIPUS irradiation served as controls. The pain intensity on visual analog score was significantly decreased after 24-week LIPUS treatment. Skin perfusion pressure was significantly increased in patients who received LIPUS treatment. There was no significant difference in symptoms and perfusion parameters in the control group. No severe adverse effects were observed in any of the patients who underwent LIPUS treatment. LIPUS is noninvasive, safe and effective option for improving symptoms in patients with Buerger disease.

Short-term efficacy of endovascular procedures for lower extremity thromboangiitis obliterans (Buerger's disease).

PURPOSE: Although thrombolysis obliterans (TAO) has been recognized for more than a century, there is no optimal treatment for this disease. The aim of this report was to compare the short-term efficacies of catheter-directed thrombolysis (CDT), percutaneous transluminal angioplasty (PTA) and CDT+PTA in treating TAO disease. METHOD: Consecutive patients with TAO treated at Ganzhou People's Hospital between 2012 and 2022 were included in this retrospective study. According to the information provided in the medical records, endovascular procedures included CDT, PTA or CDT+PTA. One-year follow-up outcomes of the patients with TAO who underwent endovascular procedures were compared. The primary outcome was major adverse limb event (MALE) and the secondary outcomes were the technical success, complications, ABI at 1 week after surgery and minor amputation. RESULTS: Sixty-nine patients with TAO were assessed for inclusion in our single-center study from 2012 to 2022 and received endovascular procedures. Among them, 22 patients underwent CDT, 21 patients underwent PTA, and 26 patients underwent PTA+CDT. The one-year follow-up revealed significant differences in the MALE-free survival rates among the three groups, particularly between the CDT group and the PTA+CDT group (the hazard ratio (HR) for MALE-free survival was 0.173, 95% CI [0.050-0.599], p = 0.006). The technical success rates of the three groups were 63.6%, 90.5%, and 92.3%, respectively. There were differences in the ABI at one week after surgery among the three groups. CONCLUSIONS: Endovascular procedures are effective for TAO in the short term. The effectiveness of CDT alone is suboptimal; combining CDT with PTA achieves the most favorable endovascular treatment outcome; while the effectiveness of PTA falls in between these two procedures.

Top 100 cited articles in the thromboangiitis obliterans: a bibliometric analysis and visualized study.

OBJECTIVE: Thromboangiitis obliterans (TAO) is one of the most common types of peripheral arterial disease (PAD). This study aimed to explore the characteristics of the top 100 most cited articles in the TAO. METHODS: A bibliometric analysis based on the Web of Science (WOS) database was performed. Literature was retrieved and ranked by the citations. Listed below are the top 100 citations, including original articles, reviews, full-length proceeding papers, and case reports that were included for analysis. The type of literature, research areas, and languages were recorded. The trends of citations including the total citations, an analysis of publication and citation numbers were conducted each year. We analyzed citations from highly cited countries, authors, institutions, and journals. Research hotspots were gathered by a visualized analysis of author keywords. RESULTS: Most of the highly cited literature was original articles. A rising trend was observed in the number of citations per year. The peaks in the number of highly cited articles appeared in the year 1998 and 2006. The majority of the articles focused on the cardiovascular system and surgery. Journal of Vascular Surgery published most of the highly cited articles. The USA and Japan contributed nearly half the number of highly cited articles. Mayo Clinic and Nagoya University were highly cited institutions. Shionoya S and Olin JW were both the author with the largest number of citations and the most highly cited author in the reference. Articles that were highly cited most often addressed the following topics: "vasculitis", "autoimmune disease", and "critical limb ischemia". Keywords that were mostly used in recent years were "stem cell therapy", "progenitor therapy", and "immunoadsorption". The detection of bursts of author keywords showed the following: "permeability", "differentiation", and "critical limb ischemia" are recent keywords that have burst. CONCLUSIONS: In this study, the highly cited contributors in the field of TAO research were identified. Most cited articles in the top 100 focused on the cardiovascular system and surgery. Treatment and pathophysiology including stem cell therapy, progenitor therapy, genetics, autoimmunity, and inflammation are the hotspots of TAO.

Management of Buerger's disease during pregnancy.

Buerger's disease (BD), also known as thromboangiitis obliterans, is a non-atherosclerotic inflammatory disorder of unknown aetiology that affects small-sized and medium-sized vessels of the extremities. It is usually observed in middle-aged adults, especially those who smoke or use tobacco products. This condition is more frequently observed in men, although recent findings indicate an increasing prevalence among women, potentially due to increased cigarette use. The association between pregnancy and BD is rare, with only a few published cases. Previous reports have indicated that BD may worsen during gestation due to the characteristic hypercoagulable state of pregnancy. In addition, it seems to be associated with intrauterine growth restriction secondary to infarction of placental vessels. Careful obstetric management of maternal and fetal status is mandatory in pregnancies complicated with BD. We report a successful case of a pregnancy in a patient with BD treated with low-molecular-weight heparin.

A Multicenter Prospective Interventional Trial of Therapeutic Angiogenesis Using Bone Marrow-Derived Mononuclear Cell Implantation for Patients With Critical Limb-Threatening Ischemia Caused by Thromboangiitis Obliterans.

BACKGROUND: Thromboangiitis obliterans (TAO) can lead to the development of critical limb-threatening ischemia (CLTI). Despite conventional treatments, such as smoking cessation or revascularization, young patients (<50 years) still require limb amputation. Therapeutic angiogenesis using bone marrow-derived mononuclear cell (BM-MNC) implantation has been tested and shown to have reasonable efficacy in CLTI. In this multicenter prospective clinical trial, we evaluated the safety and efficacy of BM-MNC implantation in CLTI patients with TAO.Methods and Results: We enrolled 22 CLTI patients with skin perfusion pressure (SPP) <30 mmHg. The primary endpoint of this trial is the recovery of SPP in the treated limb after a 180-day follow-up period. Secondary endpoints include the pain scale score and transcutaneous oxygen pressure (TcPO2). One patient dropped out during follow-up, leaving 21 patients (mean age 48 years, 90.5% male, Fontaine Class IV) for analysis. BM-MNC implantation caused no serious adverse events and increased SPP by 1.5-fold compared with baseline. Surprisingly, this effect was sustained over the longer term at 180 days. Secondary endpoints also supported the efficacy of this novel therapy in relieving pain and increasing TcPO2. Major amputation-free and overall survival probabilities at 3 years among all enrolled patients were high (95.5% and 89.5%, respectively). CONCLUSIONS: BM-MNC implantation showed safety and significant efficacy in CLTI patients with TAO.

The Effect of Smoking Cessation on the Technical Success of Endovascular Treatment for Thromboangiitis Obliterans.

PURPOSE: To show that smoking cessation improves the technical success of lower extremity endovascular treatment in patients with thromboangiitis obliterans (TAO), or Buerger disease. MATERIALS AND METHODS: One hundred two patients with TAO who underwent endovascular treatment for chronic limb-threatening ischemia or severe claudication of lower extremities in a tertiary hospital between 2015 and 2022 were included in this retrospective study. Data on serum cotinine levels were available for the last 45 patients, and 38 patients constituted the study population. Per the institution's protocol, patients were instructed to quit smoking 15 days before the intervention. However, cotinine levels showed that some of the patients continued smoking. Technical and recanalization successes were assessed as the primary end points. The secondary end point was the improvement in Rutherford scores at the 1-month follow-up. The McNemar test was used to compare the proportion of recanalized arteries after the intervention. RESULTS: Thirty-seven men and 1 woman (mean age, 42.9 years ± 10.1) were evaluated. The overall technical success rate was 86.8% in the study group. The technical success rate was significantly higher in the nonsmoker group (n = 24 [96%]) than in the smoker group (n = 8 [61.5%]; P = .006). One-month clinical data were available for 100% of the patients. The Rutherford category of the nonsmoker group was significantly lower at the 1-month follow-up. In addition, the Wilcoxon signed-rank test revealed lower Rutherford scores after the intervention in the nonsmoker group. The adverse event rate was 8%. One (2.7%) patient in the smoker group underwent a minor amputation. CONCLUSIONS: Cessation of smoking before endovascular therapy improved technical success and recanalization rates in patients with TAO.

A systematic review and meta-analysis of early and late outcomes after endovascular angioplasty among patients with thromboangiitis obliterans and chronic limb ischemia.

BACKGROUND: No consensus has yet been reached regarding the optimal treatment of patients with thromboangiitis obliterans (TO) and chronic limb ischemia. In the present study, we aimed to summarize the results on endovascular treatment of such patients. METHODS: We performed a meta-analysis using the following databases: PubMed, Scopus, and the Cochrane Library. The eligible studies had been reported up to December 2021 and had evaluated endovascular angioplasty to treat patients with TO and chronic limb ischemia. The early (mortality and technical success) and late (primary/secondary patency and limb salvage) outcomes were evaluated. StatsDirect (StatsDirect Ltd, Merseyside, UK) was used for the statistical analysis. RESULTS: Overall, 15 eligible studies were included (only endovascular in 11 studies and both endovascular and open repair in 4 studies). Among 601 patients, 402 endovascular procedures (416 limbs) were recorded (angioplasty plus stenting for 7.2% and angioplasty plus thrombolysis for 3.7%). The clinical presentation was intermittent claudication (stage II-III) for 7.9% of the patients and critical ischemia (stage IV-VI) for 92.1% of the patients. Most of the patients had had lesions below the knee, and five had had upper extremity lesions. The pooled technical success rate was 86% (range, 81.1%-90.3%), with no in-hospital mortality. The other complications included perforations (1.9%), wound complications (2.2%), and distal embolism (0.2%). Primary patency was 65.7% (range, 52.7%-77.6%) at 12 months and 50.7% (range, 23.3%-77.9%) at 36 months. Secondary patency was 76.2% (range, 57.5%-90.8%) at 12 months and 64.5% (range, 32.3%-90.6%) at 36 months. The limb salvage rate was 94.1% (range, 90.7%-96.7%) at 12 months and 89.1% (range, 80.6%-95.4%) at 36 months. CONCLUSIONS: Endovascular angioplasty for patients with TO and chronic limb ischemia was associated with optimal safety and low complication rates. The technical success and late outcomes were acceptable.

Phase IV postmarketing surveillance study shows continued efficacy and safety of Stempeucel in patients with critical limb ischemia due to Buerger's disease.

Buerger's disease or thromboangiitis obliterans is a type of obstructive vascular diseases categorized as vasculitis and usually present in 95% of young smoker men. The main pathogenetic mechanism is interplay between immune system and inflammation. Earlier our phase II study has shown that Stempeucel is safe when injected at 2 million cells/kg body weight by virtue of its anti-inflammatory, immunomodulatory, and angiogenetic properties. The present study was conducted to further assess the safety and efficacy of Stempeucel in critical limb ischemia due to Buerger's disease after obtaining approval from Indian FDA based on the data generated in the phase II study. This is an open label, multicenteric phase IV PMS study conducted across India with experienced vascular surgeons. Fifty patients of critical limb ischemia due to Buerger's disease with Rutherford III-5 or III-6 were included in the study and each individual received a dose of 2 million cells/kg body weight of Stempeucel in the calf muscles and around the ulcer. These patients were evaluated over 12 months from drug administration. The present study showed the continued long term efficacy over a period of 12 months follow up in these patients corroborating the result obtained in the previous phase II studies. There was significant improvement in rest pain, ankle systolic pressure, and ankle brachial pressure index with accelerated ulcer healing. In conclusion, the present study shows that the intramuscular administration of Stempeucel continues to be safe, tolerable, and effective alternative treatment in patients with Buerger's disease.

Milestones in thromboangiitis obliterans: a position paper of the VAS-European independent foundation in angiology/vascular medicine.

Even today thromboangiitis obliterans has disease features that remain misunderstood or underappreciated. The epidemiology, etiology and pathophysiology of the disease are still unclear. Biomarkers and disease activity markers are lacking, thus clinical assessment is difficult. We are still struggling to establish unique diagnostic, staging and treatment criteria. This is an academic-collaborative effort to describe the pathophysiology, the clinical manifestations, the diagnostic approach, and the challenges of management of patients with TAO. A systematic search for relevant studies dating from 1900 to the end of 2020 was performed on the PubMed, SCOPUS, and Science Direct databases. Given the intriguing nature of presentation of TAO, its management, to some extent is not only different in different regions of the world but also varies within the same region. Following this project, we discovered ambiguity, overlap and lack of clear-cut criteria for management of TAO. An international group of experts however came to one conclusion. They all agree that management of TAO needs a call for action for a renewed global look with multi-center studies, to update the geographical distribution of the disease and to establish a unique set of diagnostic criteria and a consensus-based guideline for best treatment based on current evidence.

Thromboangiitis Obliterans Biomarker Shifts in Different Acute Phase Stages: A Case Study.

Thromboangiitis obliterans (TAO) is a rare vasculopathy that is predominantly seen in young male smokers. Recently, new biomarkers have been shown to be useful in distinguishing TAO from acute phase TAO in an Asian study population. The present case study illustrates their application in a European patient during TAO exacerbation and their association with therapeutic performance.

Risk Factors, Mechanisms and Treatments of Thromboangiitis Obliterans: An Overview of Recent Research.

BACKGROUND: Thromboangiitis obliterans (TAO) is a nonatherosclerotic thromboticocclusive vasculitis that affects the vessels of the small and medium-sized extremities. No explicit etiology or pathogenesis of TAO has been proven, and more effective treatments are needed. OBJECTIVE: The study aimed to summarize and present an overview of recent advances regarding the risk factors, mechanisms and treatments of TAO and to organize the related information in figures to provide a comparatively complete reference. METHODS: We searched PubMed for English-language literature about TAO without article type limits, including articles about the risk factors, pathological mechanisms and treatments of TAO in the last 10 years with essential supplements (references over ranges and English abstracts of Russian literature). RESULTS: After screening content of works of literature, 99 references were evaluated. We found that risk factors of TAO include smoking, gene factors and periodontal diseases. The underlying mechanism of TAO involves oxidative stress, immunity, hemodynamic changes, inflammation and so on. Moreover, similarities in genetic factors and cigarette relevance existed between periodontal diseases and TAO, so further study of relationship was required. For TAO treatment, medicine, endovascular intervention and revascularization surgery, autologous cell therapy and novel therapies were also mentioned. Besides, a hypothesis that infection triggers autoimmunity in TAO could be speculated, in which TLR4 plays a key role. CONCLUSION: 1. A hypothesis is put forward that infections can trigger autoimmunity in TAO development, in which TLR4, as a key agent, can activate immune signaling pathways and induce autoimmune cytokines expression. 2. It is suggested to reconsider the association between periodontal diseases and TAO, as they share the same high-risk population. Controlling periodontal disease severity in TAO studies may provide new clues. 3. For TAO treatment, endovascular intervention and autologous cell therapy both showed promising long-term therapeutic effectiveness, in which autologous cell therapy is becoming more popular, although more clinical comparisons are needed.

Visceral bed involvement in thromboangiitis obliterans: a systematic review.

One of the challenges of thromboangiitis obliterans (TAO) management is in the patients whose other vascular beds are involved and it remains a challenge to know whether to pursue invasive procedures or to continue medical treatment for such TAO patients. The aim of this review was to investigate reports of the involvement of the visceral vessels in TAO and the related clinical manifestations, management approaches and outcomes. According to our systematic review, the frequency of published articles, the organs most commonly involved were the gastrointestinal tract, the heart, the central nervous system, the eye, the kidneys, the urogenital system, the mucocutaneous zones, joints, lymphohematopoietic system and the ear. Notably, reports of the involvement of almost all organs have been made in relation to TAO. There were several reports of TAO presentation in other organs before disease diagnosis, in which the involvement of the extremities presented after visceral involvement. The characteristics of the visceral arteries looked like the arteries of the extremities according to angiography or aortography. Also, in autopsies of TAO patients, the vascular involvement of multiple organs has been noted. Moreover, systemic medical treatment could lead to the recovery of the patient from the onset of visceral TAO. This study reveals that TAO may be a systemic disease and patients should be aware of the possible involvement of other organs along with the attendant warning signs. Also, early systemic medical treatment of such patients may lead to better outcomes and reduce the overall mortality rate.

Never Underestimate a Concomitant Repairable Inflow Lesion in Buerger's Disease!

A case of Buerger's disease is presented where percutaneous endovascular treatment of a concomitant focal stenosis in the superficial femoral artery led to immediate remission of symptoms and aided wound healing. The existence of such lesions should never be underestimated.

[Comprehensive treatment of a patient with Buerger's disease using genetically engineered complexes VEGF-165]. / Kompleksnoe lechenie patsienta s bolezn'iu Biurgera s primeneniem genno-inzhenernykh konstruktsii VEGF-165.

Buerger's disease, also known as thromboangiitis obliterans, is a severe invalidating systemic vascular disease. To one of the modern methods, which is distinguished by its radically new principles of action, as well as holding much promise for further study and application in treatment of patients with lower limb chronic ischaemia induced by thromboangiitis obliterans belongs the use of genetically engineered complexes based on vascular endothelial growth factor VEGF-165 ('Neovasculgen'). 'Neovasculgen' is a genetically engineered complex being a circular DNA (native plasmid on the CELO vector and Ad5), carrying the human VEGF-165 gene, encoding VEGF synthesis. Injection of this drug to the ischaemised tissues of lower extremities ensures long-term synthesis of vascular endothelial growth factor 165 leading to the development of an additional collateral vascular network and consequently to increased perfusion of tissues with oxygen and decreased degree of ischaemia. Presented herein is a clinical case report of a successful therapeutic outcome achieved in a patient suffering for a long time from thromboangiitis obliterans (Buerger's disease) and treated with genetically engineered complexes based on vascular endothelial growth factor ('Neovasculgen') used as a component of comprehensive conservative therapy.

Endovascular Recanalization of Thromboangiitis Obliterans (Buerger's Disease) in Twenty-Eight Consecutive Patients and Combined Antegrade-Retrograde Intervention in Eight Patients.

PURPOSE: The aim of the study was to evaluate the technical success of the procedure and the clinical efficacy of treatment in patients with thromboangiitis obliterans (TAO) (Buerger's disease) based on a change in the Rutherford classification. MATERIALS AND METHODS: A total of 28 consecutive patients (26 males, 2 females, mean age 43.3 ± 5.32 years) underwent endovascular recanalization with a diagnosis of TAO, between April 2015 and July 2018. After unsuccessful attempts using the antegrade approach, retrograde approaches were used in 8 patients under ultrasound guidance. Clinical follow-up was routinely performed at 1-month, 3-month, 6-month, and 1-year intervals. RESULTS: A total of 28 TAO patients underwent 40 procedures in 32 limbs. Technical success was achieved in 28 of the 32 limbs (87.5%). In total, 45 of 59 (76.2%) below the knee arteries were treated successfully. One major amputation was performed, providing a 96.8% rate for limb salvage both at 12 and 24 months. Amputation-free survival estimated by Kaplan-Meier analysis was 84% at 12 and 24 months. Primary patency rates at 12, 24, and 36 months were 84%, 78%, and 75%, respectively. Secondary patency rates were 87.5% both at 12 and 24 months. CONCLUSION: Endovascular treatment is a technically feasible and potentially effective treatment modality for Buerger's disease. Combined antegrade and retrograde interventions in TAO patients may improve technical success and clinical recovery, especially in cases where the antegrade approach has failed.

Long-term follow-up of patients with Buerger's disease after autologous stem cell therapy.

OBJECTIVE: We investigated the long-term results of autologous bone marrow mononuclear cells (ABMMNCs) implantation in patients with Buerger's disease (BD). METHODS: Twenty-eight patients (25 males and 3 females) who had BD and critical unilateral limb ischemia were investigated between April 2003 and August 2005. The patients were administered multiple injections of CD34+ and CD45+ positive ABMMNCs into the gastrocnemius muscle, the intermetatarsal region, and the dorsum of the foot (n=26) or forearm (n=2) and saline injection into the contralateral limb. RESULTS: The mean follow-up time was 139.6±10.5 months. No complication related to stem cell therapy was observed during the follow-up. The ankle-brachial pressure index evaluated at 6 months and 120 months was compared to the baseline scores (p<0.001 and p=0.021, respectively). Digital subtraction angiography (DSA) was performed for all patients at baseline, 6 months, and 120 months. The angiographic improvement was 78.5% and 57.1% at 6 and 120 months, respectively. Patients demonstrated a significant improvement in the quality of life parameters at 6 months compared to baseline (p=0.008) and 120 months compared to the baseline (p=0.009). The 10-year amputation-free rate was 96% (95% CI=0.71-1) in ABMMNC-implanted limbs and 93% (95% CI=0.33-0.94) in saline-injected limbs (p=1). CONCLUSION: Autologous stem cell therapy could be an alternative therapeutic method for BD at long-term follow-up.

Clinical outcomes of extended endovascular recanalization of 16 consecutive Buerger's disease patients.

OBJECTIVE: Buerger's disease is one of the worst diseases causing peripheral artery occlusions (especially lower extremity) with increased morbidity and mortality. Endovascular treatment of the diseased arteries gains preference over bypass surgery nowadays. Here, we aimed to present the clinical outcomes of 16 consecutive Buerger's disease patients underwent extended endovascular recanalization which is a new technique to restore direct blood flow to at least one foot artery, with the performance of angioplasty for each tibial and foot artery obstructions. METHODS: A total of 16 consecutive patients with confirmed diagnosis of Buerger's disease that percutaneously treated in our center between February 2014 and March 2018 were included in the study. The mean age of the patients was 44.25 ± 4.28 ranging from 36 to 50 years. After physical examination and complementary diagnostic tests, performance of extended angioplasty for occluded arteries was intended to restore direct blood flow to at least one of the blow-the-knee arteries. RESULTS: A successful extended endovascular treatment was performed in 20 of 22 limbs, achieving a technical success of 91%. All patients were successfully discharged without any complication. Mean follow-up duration was 21.43 ± 7.08 months. Reintervention was performed in one patient and minor amputation was needed in one of the failed limbs. Limb salvage rate was 100%. A significant difference was observed based on Rutherford classification, ankle brachial index, direct blood flow to foot, presence of ulcer and rest pain when compared before and after the intervention. CONCLUSION: We showed successful extended endovascular recanalization of Buerger's disease patients with a high technical success rate and sustained clinical improvement. Extended endovascular recanalization could be a therapeutic option in Buerger's disease patients, since they are not good candidates for surgery.