Prospects of stem cell therapy for diabetic microvascular complications.

The expectations for the clinical application of stem cell therapy for diabetic microvascular complications are increasing, as stem cell transplantation improves histopathological abnormalities mainly through angiogenesis/protection, nerve elongation/protection, and anti-inflammatory effects.

Human umbilical cord-derived mesenchymal stem cells not only ameliorate blood glucose but also protect vascular endothelium from diabetic damage through a paracrine mechanism mediated by MAPK/ERK signaling.

BACKGROUND: Endothelial damage is an initial step of macro- and micro-vasculature dysfunctions in diabetic patients, accounting for a high incidence of diabetic vascular complications, such as atherosclerosis, nephropathy, retinopathy, and neuropathy. However, clinic lacks effective therapeutics targeting diabetic vascular complications. In field of regenerative medicine, mesenchymal stem cells, such as human umbilical cord-derived MSCs (hucMSCs), have great potential in treating tissue damage. METHODS: To determine whether hucMSCs infusion could repair diabetic vascular endothelial damage and how it works, this study conducted in vivo experiment on streptozotocin-induced diabetic rat model to test body weight, fasting blood glucose (FBG), serum ICAM-1 and VCAM-1 levels, histopathology and immunohistochemical staining of aorta segments. In vitro experiment was further conducted to determine the effects of hucMSCs on diabetic vascular endothelial damage, applying assays of resazurin staining, MTT cell viability, wound healing, transwell migration, and matrigel tube formation on human umbilical vein endothelial cells (HUVECs). RNA sequencing (RNAseq) and molecular experiment were conducted to clarify the mechanism of hucMSCs. RESULTS: The in vivo data revealed that hucMSCs partially restore the alterations of body weight, FBG, serum ICAM-1 and VCAM-1 levels, histopathology of aorta and reversed the abnormal phosphorylation of ERK in diabetic rats. By using the conditioned medium of hucMSCs (MSC-CM), the in vitro data revealed that hucMSCs improved cell viability, wound healing, migration and angiogenesis of the high glucose-damaged HUVECs through a paracrine action mode, and the altered gene expressions of IL-6, TNF-α, ICAM-1, VCAM-1, BAX, P16, P53 and ET-1 were significantly restored by MSC-CM. RNAseq incorporated with real-time PCR and Western blot results clarified that high glucose activated MAPK/ERK signaling in HUVECs, while MSC-CM reversed the abnormal phosphorylation of ERK and overexpressions of MKNK2, ERBB3, MYC and DUSP5 in MAPK/ERK signaling pathway. CONCLUSIONS: HucMSCs not only ameliorated blood glucose but also protected vascular endothelium from diabetic damage, in which MAPK/ERK signaling mediated its molecular mechanism of paracrine action. Our findings provided novel knowledge of hucMSCs in the treatment of diabetes and suggested a prospective strategy for the clinical treatment of diabetic vascular complications.

Intra-lesionally autologous stem cell application in diabetic foot/ulcer.

The diabetic fot/ulcer is the cause of high morbidity and mortality in patients with diabetes mellitus (DM). Generally, medical treatment of diabetic foot/ulcer is ineffective and stem cell implantation is an important option in the treatment. Here, we present a 69 years old man admitted to hospital due to a 3 × 4 cm wound in the plantar surface of left foot. Autologous stem cells were applied intralesionally into diabetic ulcers. The lesion shrunken 50 % at the 16th week and there is a wound under the left foot at 32nd week. Intralesionally autologous stem cell application was useful and safe without adverse course in patients with diabetic foot/ulcer.

Glycemic Control Status and Long-Term Clinical Outcomes in Diabetic Chronic Total Occlusion Patients: An Observational Study.

BACKGROUND: Whether good glycemic control can result in clinical benefits for diabetic chronic total occlusion (CTO) patients is still a matter of debate. METHODS: We studied 1029 diabetic CTO patients. Based on one-year glycosylated hemoglobin A (HbA1c) levels, we assigned the patients into 2 groups: HbA1c<7% group (n = 448) and HbA1c ≥ 7% group (n = 581). We further subdivided the patients into the successful CTO revascularization (CTO-SR) and nonsuccessful CTO revascularization (CTO-NSR) groups. Kaplan-Meier analysis and Cox regression before and after propensity score matching were used to compare major adverse cardiovascular events (MACE) and other endpoints. RESULTS: There were no significant differences between the groups in terms of most endpoints in the overall patients. After propensity score-matched analysis, patients with HbA1c < 7.0 tended to be superior in terms of MACE, which was mainly attributed to repeat revascularization but the other endpoints. Furthermore, the benefit of the HbA1c < 7 group was more prominent among patients with CTO-NSR in terms of MACE, repeat revascularization, and target vessel revascularization (TVR); and the improvement of the HbAc1 < 7 group was more prominent among patients without chronic heart failure (CHF) (P=0.027). CONCLUSIONS: HbA1c < 7.0 was associated with a reduced incidence of MACE, which was mainly attributed to a reduction in repeat revascularization. Good glycemic control can improve diabetic CTO patients' clinical prognosis, especially in CTO-NSR patients.

Effects of a Catechol-Functionalized Hyaluronic Acid Patch Combined with Human Adipose-Derived Stem Cells in Diabetic Wound Healing.

INTRODUCTION: Chronic inflammation and impaired neovascularization play critical roles in delayed wound healing in diabetic patients. To overcome the limitations of current diabetic wound (DBW) management interventions, we investigated the effects of a catechol-functionalized hyaluronic acid (HA-CA) patch combined with adipose-derived mesenchymal stem cells (ADSCs) in DBW mouse models. METHODS: Diabetes in mice (C57BL/6, male) was induced by streptozotocin (50 mg/kg, >250 mg/dL). Mice were divided into four groups: control (DBW) group, ADSCs group, HA-CA group, and HA-CA + ADSCs group (n = 10 per group). Fluorescently labeled ADSCs (5 × 105 cells/100 µL) were transplanted into healthy tissues at the wound boundary or deposited at the HA-CA patch at the wound site. The wound area was visually examined. Collagen content, granulation tissue thickness and vascularity, cell apoptosis, and re-epithelialization were assessed. Angiogenesis was evaluated by immunohistochemistry, quantitative real-time polymerase chain reaction, and Western blot. RESULTS: DBW size was significantly smaller in the HA-CA + ADSCs group (8% ± 2%) compared with the control (16% ± 5%, p < 0.01) and ADSCs (24% ± 17%, p < 0.05) groups. In mice treated with HA-CA + ADSCs, the epidermis was regenerated, and skin thickness was restored. CD31 and von Willebrand factor-positive vessels were detected in mice treated with HA-CA + ADSCs. The mRNA and protein levels of VEGF, IGF-1, FGF-2, ANG-1, PIK, and AKT in the HA-CA + ADSCs group were the highest among all groups, although the Spred1 and ERK expression levels remained unchanged. CONCLUSIONS: The combination of HA-CA and ADSCs provided synergistic wound healing effects by maximizing paracrine signaling and angiogenesis via the PI3K/AKT pathway. Therefore, ADSC-loaded HA-CA might represent a novel strategy for the treatment of DBW.

A meta-analysis of everolimus-eluting stents versus sirolimus-eluting stents and paclitaxel-eluting stents in diabetic patients.

OBJECTIVE: We performed this meta-analysis to determine which stent among everolimus eluting stents (EES), sirolimus eluting stents (SES) and paclitaxel eluting stents (PES) should be preferred for the treatment of DM patients. METHODS: A systematic search of publications about randomized controlled trials (RCTs) focused on diabetic patients received EES, SES or PES was conducted. We evaluated the following indicators: target vessel revascularization (TVR), target lesion revascularization (TLR), late luminal loss (LLL), stent thrombosis (ST), myocardial infarction (MI), all-cause mortality and cardiac mortality. RESULTS: EES showed obvious advantages over SES for DM patients, as it induced the lowest rate of target vessel revascularization and target lesion revascularization (TLR) (p = 0.04). In addition, EES induced lower in-segment LLL than PSE and SES and lower in-stent LLL than PES in DM patients (all p < 0.05). Moreover, EES effectively reduced all-cause mortality compared to SES (RR = 0.71, 95% CI: 0.52-0.99, p = 0.04) and MI rates compared to PES (RR = 0.44, 95% CI: 0.26-0.73, p = 0.0002). Furthermore, EES could reduce the ST rate compared with both SES (RR = 0.53, 95% CI: 0.28-0.98, p = 0.04) and PES (RR = 0.18, 95% CI: 0.07-0.51, p = 0.001). CONCLUSION: Among those three types of stents, EES should be the first recommended stent for DM patients.

The Global Anatomic Staging System Does Not Predict Limb Based Patency of Tibial Endovascular Interventions.

OBJECTIVE: Anatomic grading systems have historically been poor predictors of patency after endovascular tibial interventions. The Global Vascular Guidelines proposed a new Global Anatomic Staging System (GLASS) to estimate one-year limb-based patency (LBP). The purpose of this study was to determine the association of GLASS with LBP following endovascular tibial interventions. METHODS: We included all patients presenting to our multidisciplinary diabetic limb preservation service between 01/2012 and 8/2020 who underwent first-time endovascular tibial revascularization for chronic limb-threatening ischemia. Diagnostic angiograms were reviewed to define the preferred target artery pathway and assign a GLASS stage to each treated limb. One-year LBP was calculated and compared across GLASS stages using Kaplan-Meier curves with log-rank tests and Cox proportional hazards models. RESULTS: We performed tibial revascularization in 96 limbs (5.2% rest pain, 56.3% ulcer, 37.5% gangrene), including isolated tibial interventions in 61.5% and tibial + femoropopliteal interventions in 38.5%. 15.6% of limbs were GLASS stage 1, 28.1% were GLASS stage 2, and 56.3% were GLASS stage 3. Overall, one-year LBP was 43.2 ± 6.3%, and did not differ significantly across GLASS stages (P = 0.42). The hazard ratio for failed LBP was 1.94 (95% CI 0.70-5.41) for GLASS stage 2 and 1.49 (95% CI 0.56-3.94) for GLASS stage 3 limbs (versus GLASS stage 1). When analyzed excluding the calcium modifier, LBP remained similar across GLASS stages (P = 0.72). Major amputation was uncommon, occurring in 9.3 ± 3.4% of limbs at one year, and did not significantly differ by GLASS stage (P = 0.98). CONCLUSION: The Global Anatomic Staging System did not predict limb-based patency following tibial endovascular interventions. Given the low major amputation rates in this cohort, anatomic complexity should not preclude endovascular limb salvage efforts below the knee.

Managing breast gangrene during the COVID-19 pandemic.

At the onset of the COVID-19 crisis, a 63-year-old woman with multiple life-limiting comorbidities was referred with a necrotic infected left breast mass on a background of breast cancer treated with conservation surgery and radiotherapy 22 years previously. The clinical diagnosis was locally advanced breast cancer, but four separate biopsies were non-diagnostic. Deteriorating renal function and incipient sepsis and endocarditis resulted in urgent salvage mastectomy during the peak of the COVID19 pandemic. The final diagnosis was infected ischaemic/infarcted breast (wet gangrene) secondary to vascular insufficiency related to diabetes, cardiac revascularisation surgery and breast radiotherapy.

Safety and Efficacy of Placenta-Derived Mesenchymal Stem Cell Treatment for Diabetic Patients with Critical Limb Ischemia: A Pilot Study.

AIM: Diabetic foot has become the main cause of non-traumatic amputation. Stem cell therapy, especially mesenchymal stem cells (MSCs), holds a great promise as a therapy for diabetic foot with ischemia limb arterial disease. The aim of this pilot study is to evaluate the safety and efficacy of placenta-derived MSCs (P-MSCs) treatment for diabetic patients with critical limb ischemia (CLI). METHODS: Four eligible diabetic patients with CLI were consecutively enrolled in this pilot study. On the base of the standard-of-care treatment, these patients accepted P-MSCs treatment by intramuscular injection for successive 3 times at an interval of 4 weeks, and the safety and efficacy of placenta-derived MSCs (P-MSCs) treatment were evaluated. RESULTS: There were no serious adverse events during the period of P-MSCs injection and the 24-weeks follow-up period. The clinical ischemic features of patients were improved 24 weeks after P-MSCs treatment. The scores of resting pain and limb coldness significantly decreased, and pain-free walking distance significantly increased from baseline to 24 weeks after P-MSCs therapy. The resting ankle brachial index increased, but no statistically significant difference was found. The findings of magnetic resonance angiography showed the increase of collateral vessel formation in one patient, but there were no significant changes observed in the other patients. CONCLUSIONS: The data in this pilot study indicated that multiple intramuscular P-MSCs injections may be a safe and effective alternative therapy for diabetic patients with CLI, and larger, placebo-controlled, perspective studies are needed to prove these results.

Evaluation of Neuropathy, Glycemic Control, and Revascularization as Risk Factors for Future Lower Extremity Amputation among Diabetic Patients.

BACKGROUND: Diabetes mellitus is a major risk factor for progression to lower extremity amputation (LEA) due to progressive neuropathy and glycemia-induced vasculopathy. In this study, we evaluated risk factors for incident LEA type 2 diabetics during a randomized controlled trial and extended post-trial follow-up. METHODS: The Action to Control Cardiovascular Risk in Diabetes trial randomized 10,251 type 2 diabetics to intensive glycemic control (Hemoglobin A1c (HbA1c) target <6.0%) versus standard glycemic control (HbA1c target 7.0-7.9%). Using backward elimination logistic regression models, we examined relationships between neuropathy using the Michigan Neuropathy Screening Instrument (MNSI) and glycemic control and incident LEA during the clinical trial and subsequent follow-up. RESULTS: 9,746 patients were followed for a mean of 7.9 +/-3.1 (median 8.9) years after randomization. Ninety-eight (1%) participants underwent an incident LEA during the trial or post-trial follow-up period. Baseline demographics and traditional risk factors were examined by incident amputation status. Multivariable models revealed that abnormal 10 gm filament test (HR 4.50, 95% CI 2.92-6.95, P < 0.0001), presence of ulceration (HR 4.22, 95% CI 1.65-10.8, P = 0.0004), abnormal appearance on foot examination (HR 4.75, 95% CI 2.30-9.83, P < 0.0001), and mean postrandomization HbA1c (HR 1.65, 95% CI 1.35-2.00, P < 0.0001) were strongly predictive of LEA when accounting for other common risk factors for amputation. CONCLUSIONS: In this post hoc analysis of a large randomized controlled population of diabetic patients, we found that components of the MNSI score including presence of ulceration, abnormal appearance of the foot, and 10 gm filament monofilament scoring were strongly predictive of LEA. This adds a valuable clinical tool in the risk stratification of diabetic patients for LEA.

Diabetes management during cardiac surgery in the UK: A survey.

AIM: To determine current practice regarding the diabetes management of people undergoing cardiac surgery in the UK. METHODS: We conducted an online survey of UK cardiothoracic surgeons. All cardiothoracic surgeons listed in the Society of Cardiothoracic Surgery membership directory were invited to participate. The survey, compiled using SurveyMonkey software, comprised 15 closed and open-ended questions about the management of people with diabetes pre- and peri-operatively. RESULTS: Sixty-two cardiothoracic surgeons from all 33 UK cardiac centres completed the survey. Of these, 44% responded that they routinely measure HbA1c preoperatively for all patients, 19% had an HbA1c threshold above which they would not operate and 21% currently undertake a point-of-care HbA1c measurement during the cardiothoracic outpatient visit. A total of 74% of respondents reported that it was 'easy' or 'very easy' to obtain a diabetes team review; diabetes nurse specialists were the members of the diabetes team working most closely with cardiac surgeons. Up to a third of the surgeons did not provide physical activity recommendations prior to admission and over 80% did not have a different preoperative or surgical diabetes protocol. Inconsistency in the responses within centres suggests that differences in practice may depend on individual surgeons rather than local policy. CONCLUSIONS: The study demonstrates there is only limited peri-operative management of diabetes in people undergoing cardiac surgery in the UK. There is an opportunity for greater involvement of the diabetes specialist team both before and during admission for surgery to improve outcomes. (Trial registration: ISRCTN10170306).

Adipose-derived stem cells promote diabetic wound healing via the recruitment and differentiation of endothelial progenitor cells into endothelial cells mediated by the VEGF-PLCγ-ERK pathway.

Adipose-derived stem cell (ADSC) therapy is a promising treatment strategy for wound healing; however, the mechanism underlying this effect remains unclear. In the present study, we aimed to explore the influence of ADSC-derived VEGF on diabetic wounds and its role in modulating endothelial progenitor cells. The effect of ADSCs and ADSC-derived VEGF in vivo was investigated using a diabetic wound healing model, and inflammatory factors, such as IL-6, IL-10, and TNF-α, were detected. RT-qPCR and western blot analysis were used to detect the expression of downstream targets. In addition, the role of ADSC-derived VEGF in modulating endothelial progenitor cells (EPCs) was investigated using EdU assay, CD-31 immunofluorescence, and Transwell assay in vitro. The results show that ADSCs accelerated diabetic wound tissue closure and decreased the expression of inflammatory factors, such as IL-6, IL-10, and TNF-α. Further molecular mechanism studies indicated that coculturing EPCs with ADSC--conditioned medium enhanced the proliferation, mobilization and differentiation of EPCs into endothelial cells. This enhancement was inhibited when the expression of the VEGF downstream signal molecules VEGFR2, PLCγ, and ERK1/ERK2 was blocked, indicating that ADSCs might accelerate diabetic wound healing through the recruitment and differentiation of EPCs mediated by VEGF. Overall, the results of the study revealed that ADSCs could promote diabetic wound healing through the recruitment and differentiation of EPCs via angiogenesis effects regulated by the VEGF-PLCγ-ERK1/ERK2 pathway and suppression of the inflammatory response. In addition, it will be helpful to establish further understanding of ADSC therapy for clinical application.

The potential role of lncRNAs in diabetes and diabetic microvascular complications.

Long noncoding RNAs (lncRNAs) are a group of noncoding RNAs that are longer than 200 nucleotides without protein-coding potential. Becasuse of which these RNAs have no significant protein-coding potential, they were initially considered as "junk-products" of transcription without biological meaning. Nevertheless, recent research advancements have shown that lncRNAs are involved in many physiological processes such as cell cycle regulation, cell apoptosis and survival, cancer migration and metabolism. This review described the function of lncRNAs and the potential underlying mechanism involved in diabetes and diabetic microvascular complications. The roles of lncRNAs in the pathogenesis of type 2 diabetes mellitus have only recently been recognized, involving hepatic glucose production and insulin resistance. We further investigated the mechanisms of lncRNAs in diabetic nephropathy (DN), including the roles of lncRNAs in mesangial cells (MCs) proliferation and fibrosis, inflammatory processes, extracellular matrix accumulation in the glomeruli and tubular injury. We also discussed the potential mechanism of lncRNAs in diabetic retinopathy (DR), including aberrant neovascularization and neuronal dysfunction. This review summarized the current knowledge of the functions and underlying mechanisms of lncRNAs in type 2 diabetes mellitus and related renal and retinal complications. Accumulating evidence suggests the potential of lncRNAs as therapeutic targets for clinical applications in the management of diabetes.

Microangiopathy: Is it relevant to wound healing in diabetic foot disease?

Chronic diabetic complications - both microvascular and macrovascular - have become serious health issues with their increasing prevalence paralleling the dramatic rise of the diabetic population worldwide. Of these complications, foot disease is a major cause of morbidity and mortality, consuming more health care resource than all other complications combined. Diabetic polyneuropathy and peripheral vascular disease constitute the two main risk factors, with trauma and foot infection being the most important initiating factors and contributors to delayed healing. Intracellular oxidative stress mediated by hyperglycaemia along with hypertension, dyslipidaemia and smoking constitute the main pathological processes in the aetiology of both macrovascular and microvascular disease. Whilst the former remains the major cause of overall mortality in diabetes, the role of microangiopathy in the pathogenesis of diabetes foot disease and its contribution to delayed wound healing in diabetes has yet to be fully understood and indeed continues to be debated. This article will review the key findings to date on structural and functional microvascular abnormalities in the diabetic foot skin and consider their contribution to impaired would healing.

Lower extremity artery disease in patients with type 2 diabetes.

Among all peripheral arterial diseases, lower extremity arterial disease is a serious condition in subjects with type 2 diabetes mellitus, associated with important disability, cardiovascular risk, and socio-economic burden. Patients with both conditions generally display poorer prognosis of affected limbs compared with non-diabetic subjects, leading to increased rates of adverse limb events including amputations. Nonetheless, awareness on lower extremity arterial disease remains somehow suboptimal in the diabetic population, partly related to an atypical clinical presentation in several cases. A regular and appropriate screening for lower extremity arterial disease in patients suffering from type 2 diabetes mellitus is therefore recommended. Affected subjects should receive optimal medical treatment including careful management of the different cardiovascular risk factors through a healthy lifestyle, a regular and structured physical activity, the administration of lipid-lowering, antidiabetic drugs, and (when indicated) antihypertensive and antithrombotic drugs. This review aims to outline current evidence about lower extremity arterial disease in patients with type 2 diabetes mellitus, in order to elucidate its epidemiology, pathophysiology, screening and diagnosis, and management options.

Effectiveness of the Combined Treatment of Functional Electrical Stimulation and Deambulation in Diabetic Arteriopathy.

OBJECTIVE: To determine whether functional electrical stimulation (FES) is able to improve ischemic pain and quality of life of patients with diabetic arteriopathy (DA) in grade-IIa Leriche-Le Fontaine. MATERIAL AND METHODS: This is a single-blinded, randomized, prospective cohort study. We included patients diagnosed with grade-IIa Leriche-Le Fontaine peripheral arterial disease in both lower extremities with and without diabetes mellitus (DM). The ankle-brachial index was 0.4-0.9. Patients were randomized into two experimental groups: nondiabetic (non-DM) (n = 71) and diabetic (DM) (n = 71). The patients received FES while walking for 1 hr on a supervised treadmill. Three months of follow-up were conducted after treatment. RESULTS: A total of 168 patients were randomized; 142 completed the study, with 71 in each group. Both groups reported an improvement after the treatment, but the improvement was statistically significant in the DM group, in which all the parameters studied improved. Greater benefits were observed in all the parameters in the DM group after the follow-up, except for the test of the meters walked in 6 min. CONCLUSIONS: The use of FES during daily walking is effective in patients with DA, reducing intermittent claudication and improving the quality of life of these patients.

Long-term Outcomes of an Endovascular-First Approach for Diabetic Patients With Predominantly Tibial Disease Treated in a Multidisciplinary Setting.

BACKGROUND: Randomized studies suggest that open lower extremity revascularization procedures are associated with improved outcomes compared with endovascular peripheral vascular interventions (PVIs). However, advances in endovascular technologies and treatment by multidisciplinary limb preservation teams have shown improved outcomes. The aim of our study was to compare perioperative and long-term outcomes after open versus PVI procedures in diabetic patients with chronic limb-threatening ischemia (CLTI) treated in a multidisciplinary setting. METHODS: All patients presenting to our multidisciplinary diabetic limb-preservation service from 6/2012 to 07/2018 were enrolled in a prospective database. Patients who underwent either an open lower extremity bypass (LEB) or a PVI for CLTI were included in the analysis. Perioperative (30-day) complications and 4-year patency and limb salvage rates were compared between PVI and LEB using chi-squared tests, Kaplan-Meier curve analyses, and stepwise multivariable Cox proportional hazards models. RESULTS: A total of 195 lower extremity revascularization procedures were performed in 120 patients (mean age: 65.0 ± 1.0 years, 61.7% male, 63.3% black), including 53 (27.2%) open procedures and 142 (72.8%) PVIs. Nearly two-thirds of procedures (65.6%) treated multilevel diseases, while 27.2% treated isolated tibial disease and 7.2% treated isolated femoropopliteal disease. More than half of the procedures (53.3%) were performed for Wound, Ischemia, and foot Infection (WIfI) classification stage 4 limbs, 25.1% for stage 3, and 21.6% for stage 1/2. In the LEB group, 67.9% of targets were infrapopliteal. In the PVI group, 63.4% of procedures were isolated tibial interventions or were multilevel interventions including the tibial segment. Perioperative complications occurred in 52.8% of LEB versus 12.0% of PVI (P < 0.001). At 4 years postoperatively, there was no significant difference in crude (unadjusted) primary patency for PVI versus LEB (34.5 ± 6.6% vs. 49.6 ± 8.1, P = 0.89). Secondary patency was better for the LEB group (50.3 ± 7.4% vs. 55.4 ± 7.5%; P = 0.04), but amputation-free survival was similar (65.1 ± 6.7% vs. 60.9 ± 9.7%; P = 0.79). After adjusting for baseline differences between groups, primary patency (hazard ratio [HR]: 0.61; 95% confidence interval [CI]: 0.34 to 1.10) and amputation-free survival (HR: 1.51; 95% CI: 0.71 to 2.34) remained similar for PVI versus LEB, but secondary patency was persistently lower for PVI (HR: 0.35; 95% CI: 0.14 to 0.90). CONCLUSIONS: In this cohort of diabetic patients with CLTI undergoing predominantly tibial interventions, open revascularization was associated with a higher risk of perioperative complications than PVIs. While secondary patency rates were better after LEBs, our data suggest that an endovascular-first approach results in equivalent long-term amputation-free survival for diabetic patients treated in a multidisciplinary setting.

Synthesis, Metabolism, and Signaling Mechanisms of Hydrogen Sulfide: An Overview.

In addition to nitric oxide (NO) and carbon monoxide (CO), hydrogen sulfide (H2S) has recently emerged as the novel gasotransmitter involved in the regulation of the nervous system, cardiovascular functions, inflammatory response, gastrointestinal system, and renal function. H2S is synthesized from L-cysteine and/or L-homocysteine by cystathionine ß-synthase, cystathionine γ-lyase, and cysteine aminotransferase together with 3-mercaptopyruvate sulfurtransferase. In addition, H2S is enzymatically metabolized in mitochondria by sulfide:quinone oxidoreductase, persulfide dioxygenase, and sulfite oxidase to thiosulfate, sulfite, and sulfate which enables to regulate its level by factors such as oxygen pressure, mitochondria density, or efficacy of mitochondrial electron transport. H2S modifies protein structure and function through the so-called sulfuration or persulfidation, that is, conversion of cysteine thiol (-SH) to persulfide (-SSH) groups. This, as well as other signaling mechanisms, is partially mediated by more oxidized H2S-derived species, polysulfides (H2Sn). In addition, H2S is able to react with reactive oxygen and nitrogen species to form other signaling molecules such as thionitrous acid (HSNO), nitrosopersulfide (SSNO-), and nitroxyl (HNO). All H2S-synthesizing enzymes are expressed in the vascular wall, and H2S has been demonstrated to regulate vascular tone, endothelial barrier permeability, angiogenesis, vascular smooth muscle cell proliferation and apoptosis, and inflammatory reaction. H2S-modifying therapies are promising approach for diseases such as arterial hypertension, diabetic angiopathy, and atherosclerosis.