Ceramides in peripheral arterial plaque lead to endothelial cell dysfunction.

Background: Peripheral arterial atheroprogression is increasingly prevalent, and is a risk factor for major limb amputations in individuals with risk factors such as diabetes. We previously demonstrated that bioactive lipids are significantly altered in arterial tissue of individuals with diabetes and advanced peripheral arterial disease. Methods: Here we evaluated whether sphingolipid ceramide 18:1/16:0 (C16) is a cellular regulator in endothelial cells and peripheral tibial arterial tissue in individuals with diabetes. Results: We observed that C16 is the single most elevated ceramide in peripheral arterial tissue from below the knee in individuals with diabetes (11% increase, P < .05). C16 content in tibial arterial tissue positively correlates with sphingomyelin (SPM) content in patients with and without diabetes (r2 = 0.5, P < .005; r2 = 0.17, P < .05; respectively). Tibial arteries of individuals with diabetes demonstrated no difference in CERS6 expression (encoding ceramide synthase 6; the predominate ceramide synthesis enzyme), but higher SMPD expression (encoding sphingomyelin phosphodiesterase that catalyzes ceramide synthesis from sphingomyelins; P < .05). SMPD4, but not SMPD2, was particularly elevated in maximally diseased (Max) tibial arterial segments (P < .05). In vitro, exogenous C16 caused endothelial cells (HUVECs) to have decreased proliferation (P < .03), increased apoptosis (P < .003), and decreased autophagy (P < .008). Selective knockdown of SMPD2 and SMPD4 decreased native production of C16 (P < .01 and P < .001, respectively), but only knockdown of SMPD4 rescued cellular proliferation (P < .005) following exogenous supplementation with C16. Conclusions: Our findings suggest that C16 is a tissue biomarker for peripheral arterial disease severity in the setting of diabetes, and can impact endothelial cell viability and function. Clinical relevance: Peripheral arterial disease and its end-stage manifestation known as chronic limb-threatening ischemia (CLTI) represent ongoing prevalent and intricate medical challenges. Individuals with diabetes have a heightened risk of developing CLTI and experiencing its complications, including wounds, ulcers, and major amputations. In the present study, we conducted a comprehensive examination of the molecular lipid composition within arterial segments from individuals with CLTI, and with and without diabetes. Our investigations unveiled a striking revelation: the sphingolipid ceramide 18:1/16:0 emerged as the predominant ceramide species that was significantly elevated in the peripheral arterial intima below the knee in patients with diabetes. Moreover, this heightened ceramide presence is associated with a marked impairment of endothelial cell function and viability. Additionally, our study revealed a concurrent elevation in the expression of sphingomyelin phosphodiesterases, enzymes responsible for catalyzing ceramide synthesis from sphingomyelins, within maximally diseased arterial segments. These findings underscore the pivotal role of ceramides and their biosynthesis enzymes in the context of CLTI, offering new insights into potential therapeutic avenues for managing this challenging disease process.

Endovascular Treatment of Thromboangiitis Obliterans (Buerger's Disease).

PURPOSE: When critical limb ischemia (CLI) occurs in patients with thromboangiitis obliterans (TAO) or Buerger's disease, smoking cessation alone may be insufficient to relieve rest pain and promote wound healing. Accordingly, adjunctive measures are warranted to restore adequate blood flow required for limb salvage. This study aimed to evaluate the feasibility and efficacy of percutaneous transluminal angioplasty (PTA) for the treatment of patients with TAO and CLI. In addition, a review of the literature on endovascular management of TAO is included. METHODS: Between April 2012 and June 2017, all patients with TAO and CLI who underwent PTA were studied retrospectively. Patient demographics, presentation, procedural details, and clinical response were recorded. Patients were monitored at 1 week, 1, 2, 3, and 6 months after revascularization and at least every 6 months thereafter. RESULTS: Thirteen patients with TAO and CLI, who presented with rest pain only (n = 1), ischemic ulcer (n = 4), or gangrene (n = 8) underwent endovascular interventions with primary and assisted primary technical success of 85% and 92%, respectively. A below-knee amputation was eventually done in the only patient with technical failure (limb salvage rate: 92%). Following the procedures, 11 patients had clinical response, one of whom also received intra-arterial vasodilator to achieve complete symptom relief. The other patient who failed PTA underwent a successful lumbar sympathectomy. In addition, all ulcers healed and eight minor amputations were performed due to already established gangrene. During follow-up (mean: 19.4 months), four patients needed reintervention. Patients who continued to smoke experienced more severe ischemia ( P = .017) and were more likely to require reintervention ( P = .009). CONCLUSION: Percutaneous transluminal angioplasty can be considered as a technically feasible and potentially effective treatment for patients with TAO and CLI, as well as a last resort for limb salvage when other options have failed. However, reintervention may be required, especially in patients who continue smoking.

Digital pressure and oxygen saturation measurements in the diagnosis of chronic hemodialysis access-induced distal ischemia.

OBJECTIVE: Hemodialysis access-induced distal ischemia (HAIDI) can be classified as acute (on the first postoperative day), subacute (≤1 month), or chronic (>1 month), based on the time of onset after access creation. The diagnosis is mainly clinical. However, performing additional tests is beneficial in further assessment of patients. The purpose of this study was to evaluate the use of finger pressure and oxygen saturation measurements for the diagnosis of chronic HAIDI. METHODS: A total of 20 patients with chronic HAIDI (cases) and 40 asymptomatic hemodialysis patients (controls) were matched for age, sex, etiology of end-stage renal disease, and type of arteriovenous access. Basal digital pressure (BDP), digital pressure during manual compression of access, digital brachial index (DBI), change in digital pressure with access compression (CDP), digital pressure of the contralateral side, and bilateral oxygen saturation (O2 Sat) were measured in all patients. RESULTS: In the case group, compression of the arteriovenous fistula (AVF) increased mean BDP from 61 ± 26 to 118 ± 28 mm Hg (P < .001), which failed to reach the non-AVF side mean digital pressure of 151 ± 25 mm Hg (P < .001). In addition, O2 Sat of the AVF side was significantly lower than the contralateral side (92.9% ± 2.1% vs 95.6% ± 1.4%; P = .001). Among the controls, manual AVF compression raised the mean BDP from 114 ± 36 mm Hg to 133 ± 29 mm Hg (P < .001), which was still significantly lower than the contralateral side mean digital pressure of 141 ± 30 mm Hg (P = .002). In addition, O2 Sat values of the two sides were different (96.7% ± 2.1% vs 97.1% ± 1.9%; P = .01). Comparing the cases and controls, the mean BDP (61 ± 26 mm Hg vs 114 ± 36 mm Hg; P < .001), DBI (0.44 ± 0.16 vs 0.82 ± 0.19; P < .001), and O2 Sat (92.9% ± 2.1% vs 96.7% ± 2.1%; P < .001) were significantly lower and CDP (57 ± 24 mm Hg vs 19 ± 17 mm Hg; P < .001) was significantly higher in the cases than in the controls. The optimal discriminatory thresholds of 80 mm Hg for BDP, 0.7 for DBI, 40 mm Hg for CDP, and 94% for O2 Sat were determined. CONCLUSIONS: Digital pressure and O2 Sat measurements are useful additional methods to assist in the clinical evaluation of hemodialysis patients with access-related hand ischemia. BDP <80 mm Hg, DBI <0.7, CDP >40 mm Hg, and O2 Sat <94% are associated with chronic HAIDI.

Chronic hemodialysis access-induced distal ischemia (HAIDI): distinctive form of a major complication.

PURPOSE: Hemodialysis access-induced distal ischemia (HAIDI) is an uncommon but potentially devastating complication. HAIDI is classified as acute, subacute and chronic based upon the time of onset. The aim of this study was to determine the prevalence, severity, patients' characteristics and the underlying etiologic mechanism of chronic HAIDI using color Doppler ultrasonography (CDUS). METHODS: Between June and August 2010, 676 hemodialysis patients with arteriovenous access (AVA) were evaluated for clinical evidence of chronic HAIDI. In the case-control part of the study, CDUS findings were compared between ischemic patients and asymptomatic matched controls. Also, patients with chronic HAIDI were followed up until February 2014, access ligation, kidney transplantation or death. RESULTS: Eighteen chronic HAIDI patients were diagnosed (2.66%). Cold hand and cold sensation were the most common signs and symptoms of hand ischemia, respectively. Fifteen patients were classified in stage 1. Patients with proximal autogenous arteriovenous fistula, younger age, more previous AVAs and less access age were more likely to develop chronic HAIDI. Excessive fistula flow was found in the majority of ischemic patients (83.3%). The mean fistula flow was significantly higher in cases compared to controls (p=0.001). Eleven patients with chronic HAIDI were successfully treated by conservative measures alone until the end of follow-up (n=3), kidney transplantation (n=4) or death (n=4). CONCLUSIONS: CDUS is a useful adjunctive diagnostic tool to determine the etiology of chronic HAIDI. Conservative measures combined with close follow-up can be used as the first step in the management of chronic HAIDI patients with mild symptoms.