Intravascular Ultrasound Use is Associated with Improved Patency in Lower Extremity Peripheral Arterial Interventions.

BACKGROUND: Intravascular ultrasound (IVUS) facilitates detailed visualization of endoluminal anatomy not adequately appreciated on conventional angiography. However, it is unclear if IVUS use improves clinical outcomes of peripheral vascular interventions (PVIs) for peripheral arterial disease. This study aimed to evaluate the impact of IVUS on 1-year outcomes of PVI in the vascular quality initiative (VQI). METHODS: The VQI-PVI modules were reviewed (2016-2020). All patients with available 1-year follow-up after lower extremity PVI were included and grouped as IVUS-PVI or non-IVUS PVI based on use of IVUS. Propensity matching (1:1) was performed using demographics and comorbidities. One-year major amputation and patency rates were compared. A generalized estimating equation model was used to identify predictors of 1-year outcomes. Subgroup analysis based on Trans-Atlantic Intersociety Consensus (TASC) classification, treatment length and treatment modalities were performed using same modeling approaches. RESULTS: There were 56,633 procedures (non-IVUS PVI = 55,302 vs. IVUS-PVI = 1,331) in 44,042 patients. Propensity matching yielded a total cohort of 1,854 patients matched (1:1), with no baseline differences. Lower extremity revascularization for claudication was performed in 60.4%, while one-third (33.9%) had chronic limb threatening ischemia (CLTI). IVUS was more commonly used for lesions >15 cm in length (46.6% vs. 43.3%) and for aortoiliac disease (31.8% vs. 27.2%). Rates of atherectomy and stenting were significantly higher with IVUS-PVI (21.1% vs. 16.8%), while balloon angioplasty was less common (13.5% vs. 24.4%). One-year patency was better with IVUS-PVI (97.7% vs. 95.2%, P = 0.004). On subgroup analysis, IVUS (odds ratio [OR] 2.20, 95% confidence interval [CI] 1.29-3.75) was associated with improved patency in CLTI patients, TASC C or D lesions, and treatment length >15 cm. Adjunctive IVUS use during PVI did not significantly impact 1-year amputation (OR 1.7, 95% CI 0.78-3.91). On multivariable regression, adjunctive use of IVUS (OR 2.46 95% CI 1.43-4.25) and aortoiliac interventions (OR 2.91, 95% CI 1.09-7.75) were independent predictors of patency. Treatment modalities such as atherectomy, stenting or balloon angioplasty did not significantly impact patency at 1-year. CONCLUSIONS: IVUS during lower extremity PVI is associated with improved 1-year patency, when compared to angiography alone. Certain subgroups, such as CLTI patients, lesions>15 cm, and TASC C or D lesions might benefit from adjunctive use of IVUS.

Sex hormones impact early maturation and immune response in the arteriovenous fistula mouse model.

Arteriovenous fistulae (AVF) fail to mature more frequently in female patients compared with male patients, leading to inferior outcomes and decreased utilization. Since our mouse AVF model recapitulates sex differences in human AVF maturation, we hypothesized that sex hormones mediate these differences during AVF maturation. C57BL/6 mice (9-11 wk) were treated with aortocaval AVF surgery and/or gonadectomy. AVF hemodynamics were measured via ultrasound (days 0-21). Blood was collected for FACS and tissue for immunofluorescence and ELISA (days 3 and 7); wall thickness was assessed by histology (day 21). Inferior vena cava shear stress was higher in male mice (P = 0.0028) after gonadectomy, and they had increased wall thickness (22.0 ± 1.8 vs. 12.7 ± 1.2 µm; P < 0.0001). Conversely, female mice had decreased wall thickness (6.8 ± 0.6 vs. 15.3 ± 0.9 µm; P = 0.0002). Intact female mice had higher proportions of circulating CD3+ T cells on day 3 (P = 0.0043), CD4+ (P = 0.0003) and CD8+ T cells (P = 0.005) on day 7, and CD11b+ monocytes on day 3 (P = 0.0046). After gonadectomy, these differences disappeared. In intact female mice, CD3+ T cells (P = 0.025), CD4+ T cells (P = 0.0178), CD8+ T cells (P = 0.0571), and CD68+ macrophages (P = 0.0078) increased in the fistula wall on days 3 and 7. This disappeared after gonadectomy. Furthermore, female mice had higher IL-10 (P = 0.0217) and TNF-α (P = 0.0417) levels in their AVF walls than male mice. Sex hormones mediate AVF maturation, suggesting that hormone receptor signaling may be a target to improve AVF maturation.NEW & NOTEWORTHY After arteriovenous fistula creation, females have lower rates of maturation and higher rates of failure than males. In a mouse model of venous adaptation that recapitulates human fistula maturation, sex hormones may be mechanisms of the sexual dimorphism: testosterone is associated with reduced shear stress, whereas estrogen is associated with increased immune cell recruitment. Modulating sex hormones or downstream effectors suggests sex-specific therapies and could address disparities in sex differences in clinical outcomes.

Arterial Diameter and Percentage of Monocytes are Sex-Dependent Predictors of Early Arteriovenous Fistula Maturation.

BACKGROUND: Arteriovenous fistulae mature less frequently in women than in men, leading to inferior patency and decreased fistula utilization in women. We hypothesized that both anatomic and physiologic sex differences explain reduced maturation. METHODS: The electronic medical records of patients who had a primary arteriovenous fistula created from 2016 to 2021 at a single center were reviewed; sample size was determined using a power calculation. Postoperative ultrasound and laboratory tests were obtained at least 4 weeks after fistula creation. Primary unassisted fistula maturation was determined up to 4 years postprocedure. RESULTS: A total of 28 women and 28 men with a brachial-cephalic fistula were analyzed. The inflow brachial artery diameter was smaller in women than in men, both preoperatively (4.2 ± 0.9 vs. 4.9 ± 1.0 mm, P = 0.008) and postoperatively (4.8 ± 0.8 vs. 5.3 ± 0.9 mm, P = 0.039). Despite similar preoperative brachial artery peak systolic velocity, women had significantly lower postoperative arterial velocity (P = 0.027). Fistula flow was reduced in women, particularly in the midhumerus (747.0 ± 570.4 vs. 1,117.1 ± 471.3 cc/min, P = 0.003). Percentages of neutrophils and lymphocytes were similar among women and men 6 weeks after fistula creation. However, women had reduced monocytes (8.5 ± 2.0 vs. 10.0 ± 2.6%, P = 0.0168). Among 28 men, 24 of 28 (85.7%) achieved unassisted maturation, whereas only 15 of 28 (53.6%) women had fistulae that matured without intervention. Secondary analysis using logistic regression suggested that postoperative arterial diameter was associated with maturation in men, while postoperative monocyte percentage was associated with maturation in women. CONCLUSIONS: Sex differences during arteriovenous fistula maturation are present in arterial diameter and velocity, suggesting that both anatomic and physiologic differences in arterial inflow contribute to sex differences in fistula maturation. In men, postoperative arterial diameter is correlated with maturation, whereas in women, the significantly lower proportion of circulating monocytes suggests a role for the immune response in fistula maturation.

Safety and efficacy of endovenous laser ablation (EVLA) using 1940 nm and radial emitting fiber: 3-year results of a prospective, non-randomized study and comparison with 1470 nm.

OBJECTIVES: To evaluate the safety, efficacy and ≥36 months outcomes of endovenous laser ablation (EVLA) by means of 1940 nm laser with radial fiber for the treatment of truncal vein insufficiency and compare the results to a historical cohort, obtained via reviewing the literature. METHODS: This prospective, non-randomized, single-center clinical study included 139 consecutive patients with 177 incompetent great saphenous (GSV, n = 135) and short saphenous veins (SSV, n = 42). The maximum laser power (Pmax. 10 W) and pullback velocity were adjusted individually (Vmax = 1 mm/s). The laser fiber was placed at the junction to the deep vein under duplex monitoring. Simultaneous phlebectomies were performed on all the patients. Regular follow up with clinical and duplex ultrasound examination (DUS) were carried out postoperatively at 1 month (1 M), 6 months (6 M), 12 months (12 M), 24 months (24 M), 36 months, and after that (≥36 M). The results were compared with three cohorts (total 616 EVLA procedures with 1470 nm laser and radial fiber) from literature (criteria: >100 procedures, follow-up of ≥2 years). RESULTS: The follow-up rate was 100%, 91%, 73%, 48%, and 23% of the truncal veins at 1, 6, 12, 24, and ≥36 M, respectively. In comparison to the literature using 1470, a lower average linear endovenous energy density (LEED) (53 vs. 77-82 J/cm) resulted in 100% (6 M) and 96.5% (24 M) occlusion rates, reduced local ecchymosis (2.2% vs. 3.2%-18.7%) and reduced average postoperative pain levels (1.3 vs. 2.18). Regarding adverse events, induration (1.1% vs. 1.8%), skin burns (0% vs. 0.45%), endovenous heat-induced thrombus propagation (EHIT) in the deep veins (2.3% vs. 1.8%) and laser-induced persistent paresthesia (2.2% vs. 0.5%-2.9%) were comparable. Recanalizations observed in this study (GSV 0, SSV 3) were asymptomatic and required no treatment. At ≥36 M reflux in the accessory veins was observed in 5% versus 10.5% of patients. Reintervention was required in none (0% vs. 21%). At >36 M, short average stump lengths of 1 cm (GSV) and 0.3 cm (SSV) were observed. CONCLUSION: EVLA with 1940 nm laser with radial emitting fiber is as safe and effective as 1470 nm laser for the treatment of truncal vein insufficiency. Lower postoperative pain, low analgesic requirements, short convalescence add to patients' comfort. EVLA with 1940 nm laser-guided by intraoperative DUS permits reproducible placement of the radial fiber at the saphenofemoral and saphenopopliteal junction, enabling further studies to assess the effect of shorter stump length on patterns and frequency of recurrence without increased risk of EHIT.

Adipose-derived mesenchymal stem cells accelerate diabetic wound healing in a similar fashion as bone marrow-derived cells.

We have previously shown that bone marrow-derived mesenchymal stem cells (BMSC) accelerate wound healing in a diabetic mouse model. In this study, we hypothesized that adipose tissue-derived stem cells (ADSC), cells of greater translational potential to human therapy, improve diabetic wound healing to a similar extent as BMSC. In vitro, the characterization and function of murine ADSC and BMSC as well as human diabetic and nondiabetic ADSC were evaluated by flow cytometry, cell viability, and VEGF expression. In vivo, biomimetic collagen scaffolds containing murine ADSC or BMSC were used to treat splinted full-thickness excisional back wounds on diabetic C57BL/6 mice, and human healthy and diabetic ADSC were used to treat back wounds on nude mice. Wound healing was evaluated by wound area, local VEGF-A expression, and count of CD31-positive cells. Delivery of murine ADSC or BMSC accelerated wound healing in diabetic mice to a similar extent, compared with acellular controls ( P < 0.0001). Histological analysis showed similarly increased cellular proliferation ( P < 0.0001), VEGF-A expression ( P = 0.0002), endothelial cell density ( P < 0.0001), numbers of macrophages ( P < 0.0001), and smooth muscle cells ( P < 0.0001) with ADSC and BMSC treatment, compared with controls. Cell survival and migration of ADSC and BMSC within the scaffolds were similar ( P = 0.781). Notch signaling was upregulated to a similar degree by both ADSC and BMSC. Diabetic and nondiabetic human ADSC expressed similar levels of VEGF-A ( P = 0.836) in vitro, as well as in scaffolds ( P = 1.000). Delivery of human diabetic and nondiabetic ADSC enhanced wound healing to a similar extent in a nude mouse wound model. Murine ADSC and BMSC delivered in a biomimetic-collagen scaffold are equivalent at enhancing diabetic wound healing. Human diabetic ADSC are not inferior to nondiabetic ADSC at accelerating wound healing in a nude mouse model. This data suggests that ADSC are a reasonable choice to evaluate for translational therapy in the treatment of human diabetic wounds.

The radiographic relationship of the femoral head, inguinal ligament, and common femoral artery bifurcation for optimal vascular access.

Objective: Common femoral artery (CFA) access is commonly used for endovascular interventions. Access site complications contribute to significant morbidity and mortality. This study characterizes the radiographic variability in the relationship of the femoral head, the inguinal ligament, and the CFA bifurcation, to identify the zone of optimal CFA access. Methods: Human cadaver dissection of the inguinal ligament and CFA bifurcation was performed. The inguinal ligament and CFA bifurcation were marked with radiopaque pins and plain anteroposterior radiographs were obtained. Radiographic measurements of the femoral head length, the distance of the top of the femoral head to the inguinal ligament, and to the CFA bifurcation were obtained. Results were reported as percentage of femoral head covered by the inguinal ligament or the CFA bifurcation relative to the top of the femoral head. A heatmap was derived to determine a safe access zone between the inguinal ligament and CFA bifurcation. Results: Forty-five groin dissections (male, n = 20; female, n = 25) were performed in 26 cadavers. The mean overlap of the inguinal ligament with the femoral head was 11.2 mm (range, -19.4 to 27.4 mm). There were no age (<85 vs ≥85 years) or sex-related differences. In 82.6% of cadaveric CFA exposures, there was overlap between the inguinal ligament and femoral head (mean, 27.7%; range, -85.7% to 70.1%), with 55.6% having a >25% overlap. In 11.1%, there was an overlap between the lower one-third of the femoral head and the CFA bifurcation. Cumulatively, heatmap analysis depicted a >80% likelihood of avoiding the inguinal ligament and CFA bifurcation below the midpoint of the femoral head. Conclusions: Significant variability exists in the relationship between the inguinal ligament, CFA bifurcation, and the femoral head, suggesting the lack of a consistently safe access zone. The safest access zone in >80% of patients lies below the radiographic midpoint of the femoral head and the inferior aspect of the femoral head.

Modalities to Deliver Cell Therapy for Treatment of Chronic Limb Threatening Ischemia.

Significance: Chronic limb threatening ischemia (CLTI) is a severe form of peripheral arterial disease (PAD) that is associated with high rates of morbidity and mortality, and especially limb loss. In patients with no options for revascularization, stem cell therapy is a promising treatment option. Recent Advances: Cell therapy directly delivered to the affected ischemic limb has been shown to be a safe, effective, and feasible therapeutic alternative for patients with severe PAD. Multiple methods for cell delivery, including local, regional, and combination approaches, have been examined in both pre-clinical studies and clinical trials. This review focuses on delivery modalities used in clinical trials that deliver cell therapy to patients with severe PAD. Critical Issues: Patients with CLTI are at high risk for complications of the disease, such as amputations, leading to a poor quality of life. Many of these patients do not have viable options for revascularization using traditional interventional or surgical methods. Clinical trials have shown therapeutic benefit for cell therapy in these patients, but methods of cell treatment are not standardized, including the method of cell delivery to the ischemic limb. Future Directions: The ideal delivery approach for stem cell therapy in PAD patients remains unclear. Further studies are needed to determine the best modality of cell delivery to maximize clinical benefits.

Inferior Mesenteric Artery Snorkel for Endovascular Treatment of a Large Degenerating Saccular Aneurysm.

Objective: Preservation of the inferior mesenteric artery (IMA) during endovascular aortic aneurysm repair (EVAR) is necessary for prevention of mesenteric ischaemia in the case of chronically occluded coeliac and superior mesenteric arteries (SMA). This case report presents an approach in a complex patient. Methods: A 74 year old man with hepatitis C cirrhosis and recent non-ST elevation myocardial infarction presented with an infrarenal degenerating saccular aneurysm (58 mm), chronically occluded SMA and coeliac artery, and 9 mm IMA with high grade ostial stenosis. He also had concomitant atherosclerosis of the aorta with a narrow distal aortic lumen of 14 mm, which tapered to 11 mm at the aortic bifurcation. Endovascular attempts to cross long segment occlusions of the SMA and coeliac artery were unsuccessful. Thus, EVAR was performed using the unibody AFX2 endograft and chimney revascularisation of the IMA using a VBX stent graft. One year follow up demonstrated regression of the aneurysm sac to 53 mm with patent IMA graft and no endoleak. Conclusion: Few reports have described techniques for endovascular preservation of the IMA, which is a necessary consideration in the context of coeliac and SMA occlusion. Because open surgery was not a good option for this patient, available endovascular options had to be weighed up. An added challenge was the exceptionally narrow aortic lumen in the context of aortic and iliac atherosclerotic disease. It was decided that the anatomy was prohibitive for a fenestrated design and extensive calcification was too limiting for gate cannulation of a modular graft. Thus a bifurcated unibody aortic endograft with chimney stent grafting of the IMA was successfully used as a definitive solution.

Cryptogenic acute lower extremities and multiorgan ischemia in an 8-year-old girl.

Pediatric acute limb ischemia is rare but can have devastating effects on children. The most common causes of acute limb ischemia in the pediatric age group are iatrogenic injury during cardiac catheterization and traumatic vessel injury. Embolic events have been described less often. We present the case of an 8-year-old girl with cryptogenic extensive bilateral lower extremity ischemia and embolization to multiple visceral organs. Our findings have highlighted the importance of interdisciplinary workup, timely intervention, and the advantage of intraoperative imaging for revascularization.

Podocyte Glucocorticoid Receptors Are Essential for Glomerular Endothelial Cell Homeostasis in Diabetes Mellitus.

Background Proteinuria and glomerular segmental fibrosis are inevitable complications of diabetic nephropathy though their mechanisms are poorly understood. Understanding the clinical characteristics and pathogenesis of proteinuria and glomerular segmental fibrosis in diabetic nephropathy is, therefore, urgently needed for patient management of this severe disease. Methods and Results Diabetes mellitus was induced in podocyte-specific glucocorticoid receptor knockout (GRPKO) mice and control littermates by administration of streptozotocin. Primary podocytes were isolated and subjected to analysis of Wnt signaling and fatty acid metabolism. Conditioned media from primary podocytes was transferred to glomerular endothelial cells. Histologic analysis of kidneys from diabetic GRPKO mice showed worsened fibrosis, increased collagen deposition, and glomerulomegaly indicating severe glomerular fibrosis. Higher expression of transforming growth factor-ßR1 and ß-catenin and suppressed expression of carnitine palmitoyltransferase 1A in nephrin-positive cells were found in the kidneys of diabetic GRPKO mice. Podocytes isolated from diabetic GRPKO mice demonstrated significantly higher profibrotic gene expression and suppressed fatty acid oxidation compared with controls. Administration of a Wnt inhibitor significantly improved the fibrotic features in GRPKO mice. The glomerular endothelium of diabetic GRPKO mice demonstrated the features of endothelial-to-mesenchymal transition. Moreover, endothelial cells treated with conditioned media from podocytes lacking GR showed increased expression of α-smooth muscle actin, transforming growth factor-ßR1 and ß-catenin levels. Conclusions These data demonstrate that loss of podocyte GR leads to upregulation of Wnt signaling and disruption in fatty acid metabolism. Podocyte-endothelial cell crosstalk, mediated through GR, is important for glomerular homeostasis, and its disruption likely contributes to diabetic nephropathy.

Loss of endothelial glucocorticoid receptor accelerates diabetic nephropathy.

Endothelial cells play a key role in the regulation of disease. Defective regulation of endothelial cell homeostasis may cause mesenchymal activation of other endothelial cells or neighboring cell types, and in both cases contributes to organ fibrosis. Regulatory control of endothelial cell homeostasis is not well studied. Diabetes accelerates renal fibrosis in mice lacking the endothelial glucocorticoid receptor (GR), compared to control mice. Hypercholesterolemia further enhances severe renal fibrosis. The fibrogenic phenotype in the kidneys of diabetic mice lacking endothelial GR is associated with aberrant cytokine and chemokine reprogramming, augmented Wnt signaling and suppression of fatty acid oxidation. Both neutralization of IL-6 and Wnt inhibition improve kidney fibrosis by mitigating mesenchymal transition. Conditioned media from endothelial cells from diabetic mice lacking endothelial GR stimulate Wnt signaling-dependent epithelial-to-mesenchymal transition in tubular epithelial cells from diabetic controls. These data demonstrate that endothelial GR is an essential antifibrotic molecule in diabetes.

A Dense Fibrillar Collagen Scaffold Differentially Modulates Secretory Function of iPSC-Derived Vascular Smooth Muscle Cells to Promote Wound Healing.

The application of human-induced pluripotent stem cells (hiPSCs) to generate vascular smooth muscle cells (hiPSC-VSMCs) in abundance is a promising strategy for vascular regeneration. While hiPSC-VSMCs have already been utilized for tissue-engineered vascular grafts and disease modeling, there is a lack of investigations exploring their therapeutic secretory factors. The objective of this manuscript was to understand how the biophysical property of a collagen-based scaffold dictates changes in the secretory function of hiPSC-VSMCs while developing hiPSC-VSMC-based therapy for durable regenerative wound healing. We investigated the effect of collagen fibrillar density (CFD) on hiPSC-VSMC's paracrine secretion and cytokines via the construction of varying density of collagen scaffolds. Our study demonstrated that CFD is a key scaffold property that modulates the secretory function of hiPSC-VSMCs. This study lays the foundation for developing collagen-based scaffold materials for the delivery of hiPSC-VSMCs to promote regenerative healing through guiding paracrine signaling pathways.

Stem cell therapy for diabetic foot ulcers: a review of preclinical and clinical research.

BACKGROUND: Diabetic foot ulcer (DFU) is a severe complication of diabetes, preceding most diabetes-related amputations. DFUs require over US$9 billion for yearly treatment and are now a global public health issue. DFU occurs in the setting of ischemia, infection, neuropathy, and metabolic disorders that result in poor wound healing and poor treatment options. Recently, stem cell therapy has emerged as a new interventional strategy to treat DFU and appears to be safe and effective in both preclinical and clinical trials. However, variability in the stem cell type and origin, route and protocol for administration, and concomitant use of angioplasty confound easy interpretation and generalization of the results. METHODS: The PubMed, Google Scholar, and EMBASE databases were searched and 89 preclinical and clinical studies were selected for analysis. RESULTS: There was divergence between preclinical and clinical studies regarding stem cell type, origin, and delivery techniques. There was heterogeneous preclinical and clinical study design and few randomized clinical trials. Granulocyte-colony stimulating factor was employed in some studies but with differing protocols. Concomitant performance of angioplasty with stem cell therapy showed increased efficiency compared to either therapy alone. CONCLUSIONS: Stem cell therapy is an effective treatment for diabetic foot ulcers and is currently used as an alternative to amputation for some patients without other options for revascularization. Concordance between preclinical and clinical studies may help design future randomized clinical trials.