Peripheral Artery Research Articles

Rapamycin increases murine lifespan but does not reduce mineral volume in the Matrix GLA Protein (MGP) knockout mouse model of medial arterial calcification.

Peripheral artery disease (PAD) is the narrowing of the arteries that carry blood to the lower extremities. PAD has been traditionally associated with atherosclerosis. However, recent studies have found that medial arterial calcification (MAC) is the primary cause of chronic limb ischemia below the knee. MAC involves calcification of the elastin fibers surrounding smooth muscle cells (SMCs) in arteries. Matrix GLA Protein (MGP) binds circulating calcium and inhibits vascular calcification. Mgp -/- mice develop severe MAC and die within 8 weeks of birth due to aortic rupture or heart failure. We previously discovered a rare genetic disease Arterial Calcification due to Deficiency in CD73 (ACDC) in which patients present with extensive MAC in their lower extremity arteries. Using a patient-specific induced pluripotent stem cell model we found that rapamycin inhibited calcification. Here we investigated whether rapamycin could reduce MAC in vivo using Mgp -/- mice as a model. Mgp +/+ and Mgp -/- mice received 5mg/kg rapamycin or vehicle. Calcification content was assessed via microCT, and vascular morphology and extracellular matrix content assessed histologically. Immunostaining and western blot analysis were used to examine SMC phenotypes and cellular functions. Rapamycin prolonged Mgp -/- mice lifespan, decreased mineral density in the arteries, and increased smooth muscle actin protein levels, however, calcification volume, vessel morphology, SMC proliferation, and autophagy flux were all unchanged. These findings suggest that rapamycin's effects in the Mgp -/- mouse are independent of the vascular phenotype.

Clinical Outcomes of Non–Stent-Based Interventions for Symptomatic Below-the-Knee Peripheral Artery Disease in the Excellence in Peripheral Artery Disease (XLPAD) Registry

BackgroundFor endovascular treatment of below-the-knee (BTK) peripheral artery disease (PAD), independently adjudicated real-world outcomes comparing non-stent (balloon angioplasty or PTA and adjunctive treatment) with or without a concomitant ipsilateral femoropopliteal (FP) artery intervention are scarce. Methods1060 patients from the multicenter XLPAD Registry between 2006-2021 with non-stent based BTK PAD intervention are included. Primary outcome: 1-year incidence of major adverse limb events (MALE), a composite of all-cause death, any amputation, or clinically driven repeat revascularization. Results566 patients underwent BTK and 494 BTK + FP interventions; 72% men, with mean age 68.4 ± 10.9 years. Diabetes mellitus is more prevalent in BTK only group (76.5% vs. 69%, p=0.006). Mean Rutherford class 4.2 ± 1.18; chronic limb threatening ischemia is more frequent in the BTK group (55.3% vs. 49%, p=0.040). Moderate to severe calcification is higher in BTK + FP (21.2% vs. 27.1%, p=0.024), so is lesion length (110.6 ± 77.3 vs. 135.4 ± 86.3 mm; p<0.001). Nearly, 81% lesions are treated with PTA. DCB (1.6% vs 14%, p<0.001) and atherectomy (38% vs. 58.5%; p<0.001) use is greater in BTK + FP. Procedural success is higher in BTK + FP group (86% vs. 91%, p=0.009), with amputation being the most common complication at 3.3% ≤30 days. One-year MALE (21.2% vs. 22.3%, p=0.675) and mortality (4.6% vs. 3.4%; p=0.3) are similar across BTK and BTK + FP groups. ConclusionNon-stent treatment for BTK PAD with concomitant FP intervention leads to high procedural success and similar rates of 1-year MALE compared with isolated BTK intervention. Condensed abstractThe vast majority of below-the-knee (BTK) peripheral artery disease (PAD) interventions are performed with balloon angioplasty. Presence of inflow femoropopliteal (FP) PAD in patients undergoing BTK interventions can affect the outcome of the procedure. This report explores the immediate procedural success and major adverse limb events at 1 year following balloon angioplasty treatment for isolated BTK and in those undergoing an additional FP PAD intervention.

3D-printed HA15-loaded β-Tricalcium Phosphate/Poly (Lactic-co-glycolic acid) Bone Tissue Scaffold Promotes Bone Regeneration in Rabbit Radial Defects.

In this study, a β-tricalcium phosphate (β-TCP)/poly (lactic-co-glycolic acid) (PLGA) bone tissue scaffold was loaded with osteogenesis-promoting drug HA15 and constructed by three-dimensional (3D) printing technology. This drug delivery system with favorable biomechanical properties, bone conduction function, and local release of osteogenic drugs could provide the basis for the treatment of bone defects. The biomechanical properties of the scaffold were investigated by compressive testing, showing comparable biomechanical properties with cancellous bone tissue. Furthermore, the microstructure, pore morphology, and condition were studied. Moreover, the drug release concentration, the effect of anti-tuberculosis drugs in vitro and in rabbit radial defects, and the ability of the scaffold to repair the defects were studied. The results show that the scaffold loaded with HA15 can promote cell differentiation into osteoblasts in vitro, targeting HSPA5. The micro-computed tomography scans showed that after 12 weeks of scaffold implantation, the defect of the rabbit radius was repaired and the peripheral blood vessels were regenerated. Thus, HA15 can target HSPA5 to inhibit endoplasmic reticulum stress which finally leads to promotion of osteogenesis, bone regeneration, and angiogenesis in the rabbit bone defect model. Overall, the 3D-printed β-TCP/PLGA-loaded HA15 bone tissue scaffold can be used as a substitute material for the treatment of bone defects because of its unique biomechanical properties and bone conductivity.

Safety and Efficacy of Combined Coronary and Peripheral Percutaneous Revascularization: A Proof-of-Concept Study.

Background. Lower extremity peripheral artery disease (LEPAD) frequently coexists with coronary artery disease (CAD) in patients with multisite vascular disease (MVD). While percutaneous revascularization is well-established for both LEPAD and CAD, limited evidence exists for patients eligible for both procedures. Specifically, the feasibility of concomitant LEPAD and CAD percutaneous revascularization remains unknown. Objectives. To compare the efficacy and safety of concomitant coronary and lower extremity elective percutaneous revascularization. Methods. Between 2012 and 2021, we included 135 patients in an observational, retrospective single-center registry. The population was stratified into two groups: 45 patients (concomitant group) underwent simultaneous coronary and peripheral percutaneous interventions, and 90 patients (deferred group) underwent two separate procedures within one year. The primary efficacy endpoint was major adverse cardiovascular events (MACE) at one year, while the primary safety endpoint was in-hospital contrast-induced nephropathy (CIN). Results. Study groups were well-balanced in baseline characteristics. In terms of coronary features, the concomitant revascularization group more often underwent single-vessel percutaneous coronary intervention (PCI), while the deferred group had multivessel PCI with diffuse coronary disease. No differences were detected in the number of LEPAD lesions between groups. For the primary efficacy endpoint, the incidence of MACE at one year was 37.8% in the concomitant group vs. 34.4% in the deferred group (HR 1.20, 95% CI 0.64-2.10; p = 0.61). No significant differences were found in CIN occurrence between the concomitant and deferred groups (11.1% vs. 8.9%; OR 1.30; 95% CI 0.36-4.21; p = 0.68). Conclusions. Multisite vascular disease patients eligible for CAD and LEPAD percutaneous revascularization exhibited a high cardiovascular risk profile with diffuse multivessel coronary and lower extremity disease. Our study suggests the efficacy and safety of concomitant coronary and lower extremity percutaneous revascularization based on one-year MACE incidence and in-hospital CIN. However, dedicated studies are warranted to confirm the short- and long-term outcomes of the concomitant revascularization strategy.

Abstract We111: 3D spheroids composed by induced Skeletal Muscle Progenitor Cells and Mesenchymal Stem Cells derived from human Pluripotent Stem Cells can recapitulate embryonic niches in hindlimb ischemia model

Introduction: Peripheral artery disease (PAD) is a significant comorbidity in aging population regarding diminished quality of life and increased mortality rates. There are urgent needs for developing advanced therapeutics for functional limb salvage beyond conventional revascularization. We hypothesized that 3D spheroids composed by induced Skeletal Muscle Progenitor Cells (iSKMPs) and Mesenchymal Stem Cells (iMSCs) could recapitulate embryonic niches and provide promising regenerative potentials in hindlimb ischemia (HLI) models. Methods: We manufactured scaffold-free, self-aggregated 3D spheroids using microcavity plates with ultra-low attachment surface. 3D spheroids were designed into 3 groups according to the induced cell types derived from Human Pluripotent Stem Cells (hPSCs); 1) iSKMPs only, 2) iMSCs only, 3) iSKMPs + iMSCs mixed. We transplanted 3D spheroids into the ischemic area and compared their therapeutic potentials using Laser Doppler Perfusion Imaging (LDPI) and immunohistochemical staining analysis. Results: iSKMPs secreted various angiogenic factors including IGF, HGF and FGF and facilitated tube formation and migration of endothelial cells (ECs). iSKMPs also showed the differentiation potential into myofibers in defined 2D culture condition. During the 28-day follow-up period, the transplantation of 3D mixed spheroids not only increased blood perfusion in ischemia limb, but also significantly reduced amputation rate compared with those of control and other 3D single spheroid groups. Notably, in vivo capacity of muscle regeneration was more potent in 3D mixed spheroid group with higher rate of engraftment, myotube formation, and vascularization. These findings suggested that iSKMPs played a significant role in limb salvage via myogenesis and angiogenesis, and their cell-to-cell interaction with iMSCs within 3D spheroids provided a favorable microenvironment to enhance the engraftment and maturation of iSKMPs in ischemic hindlimb. Conclusion: We demonstrated that the transplantation of 3D spheroids composed by iSKMPs and iMSCs could recapitulate developmental embryonic niches and provide potent regenerative potentials in HLI models. These findings provide compelling evidence that this injectable platform of 3D mixed spheroids can be a promising tool to rescue limb amputation in patients with PAD.

Abstract Tu023: The VEGF-A splice variants as a mechanism of impaired Inflammatory Angiogenesis in the context of advanced aging.

Background and Objectives: Aging and age-related diseases like peripheral artery disease (PAD) is associated with impairment of angiogenesis responses to injury. Critical ischemic limb and wound injury animal models have shown impact of monocytes/macrophages as a major source of angiogenic mediators leading to new arterial growth. Aging has also been associated with impairment of blood flow recovery and reduced VEGF-A expression in animals. However, recombinant VEGF-A administration or clinical trials involving VEGF-A have not fully overcome the foot perfusion and prevent limb/leg amputation. We sought to understand molecular mechanisms of reduced VEGF-A expression which remain incomplete in the context of advanced aging. Results: Firstly, in hindlimb ischemia mouse model, our data from liposomes containing-clodronate treated mice (12-weeks C57Bl6 with macrophage depletion model ) ( Fig. 1a ) demonstrate impairment of blood flow recovery compared to Control group. On day 3 post-surgery, VEGF-A and VEGF-A isoforms expression (VEGF-A 165 a and VEGF-A 165 b, respectively) were reduced in ischemic muscle. Fluorescence staining showed a reduction of macrophages (CD68 + ) was also associated with reduced endothelial cells (CD31 + ). Using a myeloid-specific and inducible deleted VEGF fl/fl mice, we then have shown a key role of early inflammatory macrophages stage as a major source of VEGF-A required for angiogenesis in young mice (Fig. 1b). Secondly, bone marrow-derived-macrophages (BMDMs) from C57Bl6 104-weeks mice also demonstrate reduced VEGF-A expression. Aged BMDMs demonstrate reduced VEGF-A 165 a while VEGF-A 165 b was highly increased. Polarized BMDMs from 12-weeks demonstrate increased VEGFR1 in “M2" macrophages while VEGFR2 was increased in “M1” macrophages. On the other hand, BMDMs from 104-weeks demonstrate reduced VEGFR2 expression while VEGFR1 was unaffected compared to young. Lastly, 104-weeks mice also demonstrate severe impairment of blood flow recovery ( Fig. 2 ) after surgery and reduced VEGF-A and VEGF-A 165 a in ischemic muscle tissue. VEGF-A 165 b was increased and both receptors, VEGF-R1/R2 levels ( Fig. 3 ) were also reduced. Fluorescence staining on day 3 post ligation demonstrates reduced endothelial cells recruitment in muscle tissue while macrophage (CD68+) number was similar. Conclusion: Our investigations will contribute to define mechanisms whereby vascular injury is associated with VEGF-A isoforms specific switch in the context of advanced aging.

Long-Term Risk of Hospitalization and Death in Patients With Mechanical Prosthetic Heart Valves

Mechanical prosthetic heart valves (MPHV) are commonly used for valvular heart disease in patients with long life expectancy. Few longitudinal data on hospitalizations specific causes in MPHV patients are available. We investigated the risk of all-cause hospitalization and mortality in MPHV patients. We performed a prospective observational ongoing study including MPHVs consecutive patients referring to the atherothrombosis outpatient clinic of the Policlinico Umberto I of Rome for the vitamin K antagonist (VKA) management. Study endpoints were all-cause, cardiovascular hospitalization and overall mortality. We included 305 MPHV patients (38.4% women, median age 60.2 years). The site of MPHV was aortic in 53.5%, mitral in 29.5% and mitro-aortic in 17%. During a median follow-up of 57.3 months, 142 hospitalizations occurred (8.16 per 100 person-years). The most common causes of hospitalization were cardiovascular disease (3.62 per 100 person-years), infections, surgery and bleeding. Predictors of cardiovascular hospitalization were atrial fibrillation (Hazard ratio [HR] 1.75, 95% confidence interval [95%CI] 1.04-2.95, p= 0.035), previous stroke/transient ischemic attack (HR 2.96, 95%CI 1.59-5.48, p=0.001) and peripheral artery disease (HR 2.42, 95%CI 1.09-5.36, p=0.030). During a median follow-up of 97.2 months, 61 deaths occurred (2.43 per 100 person-years). Age was directly associated with the risk of death (HR 1.088, 95%CI 1.054-1.122, p<0.001), while time in therapeutic range above the median was inversely associated (HR 0.436, 95%CI 0.242-0.786, p= 0.006).In conclusion, MPHV patients had a high incidence of hospitalizations, especially cardiovascular-related. The incidence of death is high, but it may be reduced by maintaining a good quality of anticoagulation.

Predicting the future caretakers of traumatic vascular injury management via operative exposure among surgical trainees

BackgroundThe management of vascular trauma requires specialized training and expertise. Although traumatic vascular injury is treated currently by both vascular and trauma surgeons in modern practice, it remains unclear who will inherit the role of managing vascular trauma in the coming decades. In this study, we examined disparities in operative experience in vascular trauma among surgical trainees across different surgical specialties. MethodsAccreditation Council for Graduate Medical Education national operative log reports were collected for graduating vascular surgery residents (VSRs), vascular surgery fellows (VSFs), and general surgery residents (GSRs) from 2012 to 2022. Total operative volume for traumatic vascular injury was examined, as were the five major contributing operative domains (neck, thoracic, abdominal, peripheral, and fasciotomy). ResultsA total of 22,052 GSRs, 334 VSRs, and 1672 VSFs graduated over the 10-year study period. VSR had the highest vascular trauma case volume (24.9 ± 3.9 cases/5 years), followed by VSF (22.1 ± 1.5 cases/2 years) then GSR (2.4 ± 0.3 cases/5 years; P < .001). Thoracic vessel exploration/repair (0.7 cases vs 0.6 cases vs 0.0 cases), abdominal vessel exploration/repair (1.0 cases vs 0.9 cases vs 0.0 cases), neck vessel exploration/repair (4.0 cases vs 3.4 cases vs 0.2 cases), peripheral vessel exploration/repair (12.1 cases vs 9.5 cases vs 1.1 cases), and lower extremity fasciotomy for trauma (7.2 cases vs 7.6 cases vs 1.1 cases) were most frequent among the VSR and VSF groups (P < .001 each). On linear regression analysis, both VSF (+0.5 cases/y; R2 = 0.81; P < .001) and GSR (+0.1 cases/y; R2 = 0.75; P = .001) groups experienced a growth in vascular trauma volume. Contrariwise, vascular trauma volume did not change among graduating VSRs (R2 = 0.13; P = .31). ConclusionsDedicated vascular surgical training provides the highest operative exposure to civilian vascular trauma in the United States.

Deep and Superficial Debridement Techniques in Lower Extremity Split-thickness Skin Grafting.

Patients with nonhealing lower extremity (LE) wounds often require a split-thickness skin graft (STSG) for closure. Nonviable tissue must be debrided before STSG inset. Our study aimed to compare differences in debridement depth on STSG outcomes. Chronic, atraumatic LE wounds receiving STSG from December 2014 to December 2022 at a single institution were reviewed. Demographics, wound characteristics, operative details, and outcomes were collected. Superficially debrided wounds were compared with wounds receiving deep debridement (DD), defined by debriding to the level of white tissue underlying the granulation tissue. Subanalysis was performed on wounds that had a negative and positive postdebridement culture. Primary outcome was graft failure. Overall, 244 wounds in 168 patients were identified. In total, 158 (64.8%) wounds were superficially debrided and 86 (35.3%) received DD. The cohort had a median Charlson Comorbidity Index of 4 [interquartile range (IQR): 3]. Diabetes (56.6%) and peripheral artery disease (36.9%) were prevalent. The only statically significant demographic difference between groups was congestive heart failure (SD: 14.9% versus DD: 3.0%, P = 0.017). Wound size, depth, and all microbiology results were similar between groups. Postoperatively, the DD group demonstrated significantly less graft failure (10.5% versus 22.2%, P = 0.023). In a multivariate regression, DD was independently associated with lower odds of graft failure (OR: 0.0; CI, 0.0-0.8; P = 0.034). Sub-analysis of graft failure supported this finding in culture-positive wounds (DD: 7.6% versus DD: 22.1%, P = 0.018) but not in culture-negative wounds (13.6% versus 22.2%, P = 0.507). The DD technique demonstrates improved outcomes in chronic, culture-positive LE wounds receiving STSG.

Molecular Imaging of Fibroblast Activation in Lower Extremity Skeletal Muscles Using a 99mTc-Labeled Inhibitor of Fibroblast Activation Protein in Porcine Model of Peripheral Artery Disease

Molecular Imaging of Fibroblast Activation in Lower Extremity Skeletal Muscles Using a 99mTc-Labeled Inhibitor of Fibroblast Activation Protein in Porcine Model of Peripheral Artery Disease

Long-term outcomes of percutaneous transluminal renal artery intervention: a retrospective study at a single center

BackgroundThe indications, benefits, and outcomes of percutaneous transluminal renal artery intervention (PTRI) remain controversial. The study purpose was to evaluate the long-term outcomes of PTRI in clinical practice.MethodsA retrospective review of 217 subjects (254 renal arteries; mean age, 59.8 years) who underwent PTRI based on medical database.ResultsThe most common cause of renal artery stenosis was atherosclerosis in 217 (85.4%), followed by Takayasu arteritis (TA) in 23 (9.1%), fibromuscular dysplasia in five (2.0%) and others in nine (3.5%). Mean follow-up duration was 5.7 ± 3.7 years. The first restenosis rate was 7.5% (n = 19; highest in TA: n = 9, 47.4%) and second restenosis occurred in six arteries (five TAs, one fibromuscular dysplasia). Follow-up blood pressure improved from 142.0/83.5 to 122.8/73.5 mmHg (P < 0.001). There was no change within 5 years’ follow-up in estimated glomerular filtration rate (P = 0.44), whereas TA changed from 69.8 ± 20.5 to 84.2 ± 17.9 mL/min/1.73 m² (P = 0.008). Progressive renal dysfunction was related to diabetes mellitus, chronic kidney disease, and peripheral artery obstructive disease on multivariate analysis with hazard ratios (95% confidence intervals) of 2.24 (1.21–4.17), 2.54 (1.33–4.84), and 3.93 (1.97–7.82), respectively.ConclusionsPTRI was associated with a blood pressure reduction. Despite a higher rate of restenosis, patients with TA showed significant improvement in estimated glomerular filtration rate. Diabetes mellitus, chronic kidney disease, and peripheral artery obstructive disease were related with progressive renal dysfunction after PTRI.

Association of Controlling Nutritional Status Score With Mortality in Patients With Chronic Limb-Threatening Ischemia Following Endovascular Revascularization

Chronic limb-threatening ischemia (CLTI) represents the severest manifestation of peripheral artery disease. Malnutrition is closely associated with poor clinical outcomes in patients with chronic diseases. The Controlling Nutritional Status (CONUT) score is a tool to evaluate the systemic inflammation and nutritional status. This study aimed to investigate the association of baseline CONUT score with mortality in patients with CLTI following endovascular revascularization. A single-center retrospective analysis of patients with CLTI undergoing endovascular revascularization between January 2015 and December 2022 was performed. Preoperative nutritional status was evaluated using CONUT score, which was calculated using the serum albumin concentration, total peripheral lymphocyte count, and total cholesterol concentration. A CONUT score ≥5 indicates moderate or severe malnutrition. The Kaplan-Meier and multivariate Cox proportional hazards regression were used for survival analysis and to evaluate the risk factors associated with mortality. Among 232 enrolled patients, 20.7% of patients had moderate or severe malnutrition defined by the CONUT score. During a median follow-up of 2.1 (interquartile ranges, 1.0-3.5) years, 87 (37.5%) patients died. The 3-year overall survival rate in patients with CLTI who underwent endovascular revascularization was 63.7%. The high CONUT (≥5) group had significantly worse 3-year overall survival (42.0% versus 68.8%, P=0.004) and limb salvage (73.3% versus 84.1%, P=0.005) rates than the low CONUT (<5) group. Multivariate analysis showed that high CONUT score was significantly associated with increased risk for mortality in patients with CLTI after endovascular revascularization (hazard ratio, 1.687; 95% confidence interval, 1.031-2.759; P=0.037). The present study indicated that moderate or severe malnutrition defined by the CONUT score was significantly associated with increased mortality in patients with CLTI following endovascular revascularization. Future study is required to evaluate the efficacy of nutritional intervention in these patients.

Prognostic impact of peripheral artery disease-related parameters in patients with acute coronary syndrome.

Lower extremity arterial disease (LEAD) and increased aortic stiffness are associated with higher mortality in patients with chronic coronary syndrome, while their prognostic significance after an acute coronary syndrome (ACS) is less known. We analyzed prevalence, clinical phenotypes and association of LEAD - assessed by the ankle-brachial index (ABI) - and increased aortic stiffness - assessed by the aortic pulse wave velocity (PWV) - with all-cause mortality and major adverse cardiovascular events (MACE) in patients admitted with an ACS. Among 270 patients admitted for ACS (mean age 67 years, 80% males), 41 (15%) had an ABI ≤0.9, with 14 of them (34%) presenting with intermittent claudication (symptomatic LEAD). Patients with symptomatic LEAD, compared with those with asymptomatic LEAD or without LEAD, had higher prevalence of cardiovascular risk factors, lower estimated glomerular filtration rate and higher high-sensitivity C-reactive protein. Patients with LEAD, either symptomatic or asymptomatic, more frequently presented with non-ST-elevation myocardial infarction and more frequently had multivessel coronary artery disease. Both symptomatic and asymptomatic LEAD were significantly associated with all-cause mortality after adjustment for confounders, including multivessel disease or carotid artery disease (hazard ratio 4.03, 95% confidence interval 1.61-10.08, P < 0.01), whereas PWV was not associated with the outcome in the univariable model. LEAD and PWV were not associated with a higher risk of MACE (myocardial infarction or unstable angina, stroke, or transient ischemic attack). LEAD, either clinical or subclinical, but not increased aortic stiffness, is an independent predictor of all-cause mortality in patients admitted for ACS.

Association of Body Surface Area versus Body Mass Index on Outcomes in Peripheral Arterial Disease

ObjectiveNumerous studies have indicated that increased obesity in patients with established peripheral artery disease (PAD) is inversely associated with disease prognosis, a phenomenon coined as the “obesity paradox”. A major cause of criticism in studies investigating the obesity paradox is the use of body mass index (BMI) as a surrogate marker in defining and quantifying the degree or severity of obesity. We conducted a retrospective review to verify whether the obesity paradox persists in patients with PAD when using body surface area (BSA) as an alternative anthropometric measure. MethodsPatients undergoing surgery (open or endovascular) for PAD between January 2009 and March 2020 were identified from the Vascular Quality Initiative (VQI) national database. The association between BSA/BMI and risk of post-operative complications was evaluated using logistic regression and restricted cubic spline analysis, both of which adjusted for demographic and comorbid risk predictors. When analyzing BSA and BMI as categorical variables, patients were grouped according to BSA quintiles and the World Health Organization (WHO) BMI categories. ResultsA total of 130,428 patients were included based on our eligibility criteria, of which 85,394 (65.5%) were men. Patients were typically hypertensive (87.8%), diabetic (50.4%), and overweight (63.0% over 25 kg/m2). Patients with a high BMI or BSA typically presented at a younger age and with greater pre-operative administration of drugs (statin, ACE-inhibitor, anticoagulant, and beta blocker). Our results indicate that BSA and BMI are inversely associated with post-operative risk of all-cause morbidity, mortality, and cardiac complications. This finding was displayed when analyzing BMI/BSA as a continuous variable, or when indexing patients into BMI/BSA groups. ConclusionOur data suggests that the obesity paradox persists in patients with PAD when using either BMI or BSA as anthropometric measures. Future studies with a prospective design and utilizing newer anthropometric indices should be conducted to fully verify the presence of this phenomenon.

Glycolytic PFKFB3 and Glycogenic UGP2 Axis Regulates Perfusion Recovery in Experimental Hind Limb Ischemia.

Despite being in an oxygen-rich environment, endothelial cells (ECs) use anaerobic glycolysis (Warburg effect) as the primary metabolic pathway for cellular energy needs. PFKFB (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase)-3 regulates a critical enzymatic checkpoint in glycolysis and has been shown to induce angiogenesis. This study builds on our efforts to determine the metabolic regulation of ischemic angiogenesis and perfusion recovery in the ischemic muscle. Hypoxia serum starvation (HSS) was used as an in vitro peripheral artery disease (PAD) model, and hind limb ischemia by femoral artery ligation and resection was used as a preclinical PAD model. Despite increasing PFKFB3-dependent glycolysis, HSS significantly decreased the angiogenic capacity of ischemic ECs. Interestingly, inhibiting PFKFB3 significantly induced the angiogenic capacity of HSS-ECs. Since ischemia induced a significant in PFKFB3 levels in hind limb ischemia muscle versus nonischemic, we wanted to determine whether glucose bioavailability (rather than PFKFB3 expression) in the ischemic muscle is a limiting factor behind impaired angiogenesis. However, treating the ischemic muscle with intramuscular delivery of D-glucose or L-glucose (osmolar control) showed no significant differences in the perfusion recovery, indicating that glucose bioavailability is not a limiting factor to induce ischemic angiogenesis in experimental PAD. Unexpectedly, we found that shRNA-mediated PFKFB3 inhibition in the ischemic muscle resulted in an increased perfusion recovery and higher vascular density compared with control shRNA (consistent with the increased angiogenic capacity of PFKFB3 silenced HSS-ECs). Based on these data, we hypothesized that inhibiting HSS-induced PFKFB3 expression/levels in ischemic ECs activates alternative metabolic pathways that revascularize the ischemic muscle in experimental PAD. A comprehensive glucose metabolic gene qPCR arrays in PFKFB3 silenced HSS-ECs, and PFKFB3-knock-down ischemic muscle versus respective controls identified UGP2 (uridine diphosphate-glucose pyrophosphorylase 2), a regulator of protein glycosylation and glycogen synthesis, is induced upon PFKFB3 inhibition in vitro and in vivo. Antibody-mediated inhibition of UGP2 in the ischemic muscle significantly impaired perfusion recovery versus IgG control. Mechanistically, supplementing uridine diphosphate-glucose, a metabolite of UGP2 activity, significantly induced HSS-EC angiogenic capacity in vitro and enhanced perfusion recovery in vivo by increasing protein glycosylation (but not glycogen synthesis). Our data present that inhibition of maladaptive PFKFB3-driven glycolysis in HSS-ECs is necessary to promote the UGP2-uridine diphosphate-glucose axis that enhances ischemic angiogenesis and perfusion recovery in experimental PAD.

Effects of Rheopheresis in dialysis patients with peripheral artery disease and diabetic foot ulcers: A multicentric Italian study.

Peripheral artery disease (PAD) in hemodialysis (HD) patients has a significant social impact due to its prevalence, poor response to standard therapy and dismal prognosis. Rheopheresis is indicated by guidelines for PAD treatment. Twenty-five HD patients affected by PAD stage IV Lerichè-Fontaine and ischemic ulcer 1C or 2C according to the University of Texas Wound Classification System (UTWCS), without amelioration after traditional medical therapy and/or revascularization, were selected and underwent 12 Rheopheresis sessions in 10 weeks. Improvements in pain symptoms using Numerical Rating Scale (NRS), healing ulcers and laboratory hemorheological parameters have been evaluated. A clinically and statistically significant mean value reduction and of relative percentage differences between estimated marginal means (Δ), calculated at each visits, of NRS was observed, with a maximum value (-48.5%) between the first and last visit. At the end of the treatment period 14.3% of ulcers were completely healed, 46.4% downgraded, 53.6% were stable. Overall, no ulcers upgraded. A statistically significant reduction of the Δ, between the first and last visit, for fibrinogen (-16%) was also observed. Rheopheresis reduced overall painful symptoms; data suggest that it could heal or improve ulcers and hemorheological laboratory parameters in HD patients with PAD and ischemic ulcers resistant to standard therapies.

Popliteal access for iliofemoral occlusive disease in the office-based catheter laboratory

ObjectivePopliteal access as an alternative to conventional femoral access has not been reported in the office-based catheter laboratory setting (OBL) and may be perceived to have higher risks. The purpose of this study was to evaluate the safety and efficacy of popliteal access for the endovascular treatment of iliofemoral arterial occlusive disease in an OBL setting. MethodsFrom October 2018 to October 2023, a total of 1408 interventions for peripheral artery disease were performed in our OBL. A cohort of 27 popliteal access consecutive procedures for femoral and iliac artery occlusions were studied. All interventions were done using a micropuncture needle under ultrasound guidance. All patients were discharged 1 hour after completion of the procedure. Indications for popliteal access were presence of aortoiliac stent grafts, aortobifemoral or aortoiliac bypasses, difficult contralateral or antegrade femoral access, and flush superficial femoral artery occlusions. Procedures were determined to be successful upon complete resolution of the target lesions and safety was measured perioperatively and at 90 days. Patency was determined clinically, by arterial duplex examination, and by need for reintervention for ≤2 years. ResultsWe performed 27 popliteal access procedures in 25 patients (21 complete femoral artery occlusions, 6 severe stenosis). Iliac disease was present in nine. Indications for popliteal access were existing aortoiliac stent graft in 11, aortobifemiliac bypass in 4, noncrossable iliac occlusions in 3, failed antegrade femoral access in 4, flush superficial femoral artery occlusion in 3, and bilateral common femoral artery disease precluding access in 2. Trans-Atlantic Inter-Society Consensus classification preoperatively was B, 4; C, 4; and D, 19. Treatments included atherectomy/balloon angioplasty and stent in 12, balloon angioplasty and stenting in 4, atherectomy/balloon angioplasty in 5, and balloon angioplasty alone in 6. Successful opening of occlusions occurred in 25 of 27 patients (92.5%). No complications or major adverse cardiac events occurred, except one asymptomatic small popliteal arteriovenous fistula. Of the 25 successful procedures, the duplex patency at 3, 6, and 12 months was 19/20 (95%), 11/15 (69.3%), and 11/13 (61%). Rutherford Classification improved from a preoperative value of >4 in 24 of 27 (89%) to a postoperative value of <2 at 1 month in 23 of 23 (100%), at 3 months in 19 of 20 (95%), at 6 months in 11 of 15 (69.3%), and at 12 months in 11 of 13 (61%). Freedom from reintervention at 3 months occurred in 19 of 20 (95%), at 6 months in 13 of 15 (86%), and at 12 months in 12 of 13 (79%). ConclusionsPopliteal artery access for complex iliofemoral disease is safe and effective and should be considered as a valid alternative option in the OBL setting.

Clinical Performance and Persistence on Dual Pathway Inhibition with Rivaroxaban and Aspirin in Real-World Setting.

The dual pathway inhibition (DPI) with low-dose rivaroxaban and aspirin in patients with stable atherosclerotic vascular disease reduces the occurrence of cardiovascular events, with no significant increase of intracranial or other critical organ bleedings. Our observational study aimed to describe the clinical performance, adherence, and persistence of DPI therapy among a real-world setting of patients with an established diagnosis of coronary artery (CAD) and/or peripheral artery disease (PAD). We prospectively included all consecutive patients with an established diagnosis of CAD and/or PAD treated with aspirin (ASA) 100 mg once daily and rivaroxaban 2.5 mg twice daily. Clinical evaluation was performed at baseline, before starting treatment, at 1 month, and every 6 months after the study drug administration. A total of 202 consecutive patients (mean age 66 ± 10 years; male 80%) eligible to DPI therapy were included. During a mean follow-up of 664 ± 177 days, the incidence rate of major bleedings and of major adverse cardiovascular events was 0.8 and 1.1 per 100 patients/year, respectively. The adherence to pharmacological treatment was 99%. Additionally, 13.4% of patients suspended the DPI therapy during the follow-up. Minor bleedings resulted the most common cause of both temporary and permanent DPI therapy discontinuation. This observational study supports the safety of DPI with low-dose rivaroxaban and aspirin among patients with CAD and PAD in a real-world setting, showing high persistence and maximum adherence to medical treatment.

Association of social support and health status outcomes in peripheral artery disease

ObjectiveA critical goal in the care of patients with peripheral artery disease (PAD) is to optimize their health status; that is, their symptoms, function, and quality of life. Social support has been proposed to be a predictor of disease-specific health status in patients with PAD. However, the prevalence of low perceived social support, the association with health status outcomes, and the interaction with other biopsychosocial variables, is unknown. Our aim was to assess the association of baseline perceived social support with health status at 12 months in patients with PAD. MethodsThe Patient-Centered Outcomes Related Treatment Practices in Peripheral Arterial Disease: Investigating Trajectories (PORTRAIT) registry, which enrolled patients with PAD in the United States, the Netherlands, and Australia from 2011 to 2015, was used. Perceived social support was assessed at baseline with the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) Social Support Inventory (ESSI), and disease-specific (Peripheral Artery Disease Questionnaire [PAQ]) and generic health status (Euro-Quality of Life Visual Analog Scale [VAS] and EQ-5D-3L Index) questionnaires were assessed at baseline and 12 months. Low social support was defined as a score of ≤3 on two items and an ESSI score of ≤18. A hierarchical mixed level linear regression model adjusting for biopsychosocial variables was used to assess the association between low perceived social support and the ESSI score with health status at 12 months. ResultsA total of 949 patients were included (mean age, 67.64 ± 9.32 years; 37.9% female), with low social support being present in 18.2%. Patients with low social support were more likely to not be married or to be living alone (50.0% vs 77.5%; P < .001); have more financial constraints; have more depressive, stress, and anxiety symptoms; and have lower disease-specific and generic health status at baseline and at 12 months. In the unadjusted model, low social support was associated with a −7.02 (95% confidence interval [CI], −10.97 to −3.07) point reduction in the PAQ, −7.43 (95% CI, −10.33 to −4.54) in the VAS, and −0.06 (95% CI, −0.09 to −0.03) in the EQ-5D-3L Index. Adjusting for biopsychosocial factors minimally attenuated these associations (PAQ: −6.52; 95% CI, −10.55 to −2.49; P = .002; VAS: −5.39; 95% CI, 8.36 to −2.42; P < .001; EQ-5D-3L Index: −0.04; 95% CI, −0.07 to 0.01; P = .022). The ESSI per-point score was associated with a decrease of 0.51 (95% CI, 0.18-0.85; P = .003) in PAQ and 0.46 (95% CI, 0.12-0.61; P = .004) in the VAS. ConclusionsAmong patients with PAD, low social support was frequent and associated with a lower health status at 1 year independent of other biopsychosocial variables. Improving social support could improve health status and outcomes in PAD.

Impact of Poor Glycemic Control and Vascular Complications on Diabetic Foot Ulcer Recurrence

Background: Diabetes mellitus is a growing global health issue that leads to serious complications like diabetic foot ulcers (DFUs), which can worsen health and increase death rates in diabetic patients. In Sorong, Southwest Papua, Indonesia, the recurrence of DFUs is a major public health problem, affecting patients' well-being and adding significant healthcare costs. This study aimed to identify the factors that contribute to DFU recurrence in this region to help improve prevention and treatment strategies. Methods: A cross-sectional study was conducted in Sorong, Indonesia, including 53 diabetic patients with recurrent DFUs. Data were collected through structured interviews, physical examinations, and laboratory tests. Risk factors such as metabolic, vascular, behavioral, and demographic elements were analyzed. Statistical analysis, including univariate, bivariate, and multivariate techniques, was performed to identify independent predictors of DFU recurrence. Results: The study found that poor glycemic control, with a mean HbA1c of 8.3±1.4, and vascular complications, such as peripheral artery disease and neuropathy, were the most significant predictors of DFU recurrence. Behavioral factors like smoking and physical inactivity, along with longer diabetes duration and previous ulcer history, also showed a strong correlation with recurrence. Logistic regression identified HbA1c levels, peripheral artery disease, and smoking habits as independent predictors. Conclusion: This study determined the need for comprehensive care that focuses on controlling blood sugar levels, managing vascular issues, and promoting healthy behaviors to prevent diabetic foot ulcer recurrence in Sorong, Southwest Papua. Future efforts should target these risk factors to lower recurrence rates and improve patient health. More research is needed to find effective ways to prevent DFU recurrence in this population.