Critical Limb-threatening Ischemia Research Articles

Clinical outcomes in patients with critical limb-threatening ischemia and infected ulcers following endovascular therapy are pathogen dependent: A single-center experience from 2012 to 2021

Clinical outcomes in patients with critical limb-threatening ischemia and infected ulcers following endovascular therapy are pathogen dependent: A single-center experience from 2012 to 2021

ThP8.1 - Long-Term Impact of COVID-19 related disruption of NHS Elective services on Emergency Major Lower Limb Amputations

Abstract Background The COVID-19 pandemic has affected the healthcare systems worldwide since the dawn of 2020. In March 2020, the United Kingdom government announced the first national lockdown which severely disturbed all NHS healthcare elective services. Our aim is to assess the long-term impact of COVID-19 related disruption of NHS elective services on emergency major lower limb amputations. Method Patients' data for emergency major lower limb amputations (MLLA) for critical limbthreatening ischemia and diabetic foot infections performed at Aberdeen Royal Infirmary was collected through Trakcare® and divided into the control pre-pandemic group (April 2018 to March 2020) and the pandemic group (April 2020 to March 2022). The statistical analysis was conducted using the IBM SPSS software [v28.0.1.1 (14)]. Results A total of 358 patients underwent MLLA and 206 (57.5%) of these had diabetes mellitus. There was a 17% increase in the number of urgent referrals and every one in five of these finally underwent an amputation. There was an increase in the absolute number of Above- and Below-Knee amputations. There was a statistically significant increase by 33% in emergency MLLAs during the pandemic period (p-value <0.05). A total of 165 postoperative deaths up to December 2022 were recorded with 30-day mortality rate of 7.26% (n=26). Conclusion NHS vascular management groups should update themselves with evolving technologies to optimise the care provided during future unprecedented times. Furthermore, more effective measures should also be implemented to avoid delayed presentations, which can potentially lead to higher rates of major limb amputations.

Evaluation of acute and midterm outcomes after complex combined antegrade/retrograde recanalization for occlusions of the femoropopliteal and infrapopliteal arteries

IntroductionWhen antegrade recanalization of femoro- and/or infrapopliteal occlusions fails, retrograde access has become an established option. To evaluate the results of combined antegrade and retrograde recanalization of femoropopliteal and infrapopliteal occlusions, patients undergoing secondary retrograde recanalization attempts were analyzed retrospectively. MethodsPrimary endpoint was the success of the procedure (successful occlusion crossing using the ante-/retrograde technique). Secondary endpoints include complication rate, primary patency and target lesion revascularization (TLR) rate, amputation rate, changes in ankle-brachial index (ABI), and Rutherford-Becker class (RBC). Predictors for procedure failure and TLR were analyzed. ResultsWe included 888 patients: 362 with femoropopliteal (group 1), 353 with infrapopliteal (group 2), and 173 with multi-level (group 3) recanalization. Critical limb threatening ischemia (CLTI) was present in group 1, 2, and 3 in 36%, 62%, and 76%, respectively. The intervention was successful in 92.5%, 93.8%, 90.8% of respective cases (p=0.455). The overall peri-interventional complication rate was 7.2%.At 6, 12 and 24 months, primary patency was highest in group 1 (63.9%, 45.8%, 33.3%), followed by group 3 (59.8%, 46.1%, 33.3%), and group 2 (58.5%, 43.1%, 30.4%), p=0.537).The risk of undergoing repeated TLR within 24 months was 31.4% for group 1, 39.1% for group 2, and 45.7% for group 3.At 24 months, the survival rate in groups 1, 2, 3 was 93.8%, 79.4% and 87.5%, respectively. During 24 months, 75 patients (8.4%) had to undergo amputation. Significant improvements in both ABI and RBC were present at discharge as well as at 6, 12 and 24 months (p<0.001).Dialysis dependency was a predictor of unsuccessful ante/retrograde recanalization (p=0.048).Lesion length (p=0.0043), dialysis (p=0.033) and recanalization level (p=0.013) increase the risk of TLR. ConclusionUsing a combined antegrade/retrograde access, recanalization of occluded femoropopliteal and/or infrapopliteal arteries can be achieved in a large number of cases. Due to the high rate of repeated TLR across all lesion localizations, the indication for ante- and retrograde recanalization may be limited to patients with CLTI.

Impact of operative approach and patient frailty on outcomes for aorto-iliac occlusive disease with critical limb threatening ischemia.

Multiple treatment modalities exist for the management of aorto-iliac occlusive disease (AIOD) including endovascular (endo), extra-anatomic bypass (EAB), and anatomic bypass (AB). The goal of this study was to examine the impact of revascularization strategy and patient frailty on outcomes for AIOD in patients with critical limb threatening ischemia (CLTI). Patients undergoing revascularization for CLTI and AIOD were identified from the NSQIP database over 5years. Demographics, procedural characteristics, and outcomes were recorded. Modified frailty index (mFI-5) was calculated for each patient. Patients were compared based on the type of procedure and frailty (mFi>0.6). From 2017 to 2021, 1777 patients underwent revascularization for CLTI from AIOD. Patients were majority male (56%) with a mean age of 68. A total of 1346 patients (76%) underwent an open operation of which 669 were EAB. When endo (431 patients) was compared with open repair, endo was associated with a higher incidence of tissue loss at presentation (42% vs 33%, p < 0.001), lower rates of bleeding (6.5% vs 15.5%, p < 0.001), fewer MI/stroke (1.6% vs 4.6%, p = 0.004), and fewer wound complications (2.6% vs 11.2%, p < 0.001). There was no difference in re-intervention, amputation, or death based on frailty. For frail patients (184 patients), type of repair did not impact re-intervention, major amputation, or mortality, though there was increased MI/stroke with EAB and increased wound complications with AB/EAB. AIOD revascularization strategies for patients with CLTI have similar 30-day re-intervention, major amputation, and mortality rates. Endovascular repair has less surgical wound complications and is better suited for frail patients.

Unraveling the differential mechanisms of revascularization promoted by MSCs & ECFCs from adipose tissue or umbilical cord in a murine model of critical limb-threatening ischemia

BackgroundCritical limb-threatening ischemia (CLTI) constitutes the most severe manifestation of peripheral artery disease, usually induced by atherosclerosis. CLTI patients suffer from high risk of amputation of the lower extremities and elevated mortality rates, while they have low options for surgical revascularization due to associated comorbidities. Alternatively, cell-based therapeutic strategies represent an effective and safe approach to promote revascularization. However, the variability seen in several factors such as cell combinations or doses applied, have limited their success in clinical trials, being necessary to reach a consensus regarding the optimal “cellular-cocktail” prior further application into the clinic. To achieve so, it is essential to understand the mechanisms by which these cells exert their regenerative properties.Herein, we have evaluated, for the first time, the regenerative and vasculogenic potential of a combination of endothelial colony forming cells (ECFCs) and mesenchymal stem cells (MSCs) isolated from adipose-tissue (AT), compared with ECFCs from umbilical cord blood (CB-ECFCs) and AT-MSCs, in a murine model of CLTI.MethodsBalb-c nude mice (n:32) were distributed in four different groups (n:8/group): control shams, and ischemic mice (after femoral ligation) that received 50 µl of physiological serum alone or a cellular combination of AT-MSCs with either CB-ECFCs or AT-ECFCs. Follow-up of blood flow reperfusion and ischemic symptoms was carried out for 21 days, when mice were sacrificed to evaluate vascular density formation. Moreover, the long-term molecular changes in response to CLTI and both cell combinations were analyzed in a proteomic quantitative approach.ResultsAT-MSCs with either AT- or CB-ECFCs, promoted a significant recovery of blood flow in CLTI mice 21 days post-ischemia. Besides, they modulated the inflammatory and necrotic related processes, although the CB group presented the slowest ischemic progression along the assay. Moreover, many proteins involved in the repairing mechanisms promoted by cell treatments were identified.ConclusionsThe combination of AT-MSCs with AT-ECFCs or with CB-ECFCs promoted similar revascularization in CLTI mice, by restoring blood flow levels, together with the modulation of the inflammatory and necrotic processes, and reduction of muscle damage. The protein changes identified are representative of the molecular mechanisms involved in ECFCs and MSCs-induced revascularization (immune response, vascular repair, muscle regeneration, etc.).

Utilization of coronary computed tomography angiography and computed tomography-derived fractional flow reserve in a critical limb-threatening ischemia cohort

Utilization of coronary computed tomography angiography and computed tomography-derived fractional flow reserve in a critical limb-threatening ischemia cohort

A fluctuating intensity of care: A qualitative study on the experiences of informal caregivers of patients with critical limb-threateningischemia.

Informal caregivers play a significant role in providing care for older, often vulnerable, patients, and supporting them as they live with chronic diseases. Due to the rising prevalence of older vascular patients and their use of healthcare, the role of their informal caregivers will become more important. However, little is known about the experiences of informal caregivers of patients with critical limb-threatening ischemia and the impact of informal care on different aspects of these caregivers' lives. In addition, literature does not describe the burden this role brings with it, or lack thereof. Therefore a qualitative study using a phenomenological approach, specifically interpretive phenomenological analysis, was used to gain insight into the experiences of the primary informal caregivers of patients with chronic limb-threatening ischemia. Data were collected via semi-structured interviews and focus groups discussions. Fifteen primary informal caregivers of patients with critical limb-threatening ischemia under the care of the vascular surgeon at a tertiary teaching hospital in the Netherlands were included. Data analysis yielded three themes: the perceived identity of this group of caregivers; the varying intensity of informal care; and the collaboration between informal carers, their care recipients and the professional care provider within the vascular surgery department. In contrast to carers of other chronic diseases, the shifting intensity of care that informal caregivers of critical limb-threatening ischemia patients experience seems to prevent long-term overload. Adapting to that fluctuating situation requires flexibility from healthcare providers within the vascular surgery department. In addition, professionals need to involve informal caregivers in the patient's decision-making process and recognize their role in that process.

The Utility of Prevena Negative Pressure Wound Therapy on Groin Incisions for Critical Limb-Threatening Ischemia: A Single Institution Experience.

Incisional negative pressure wound therapy (iNPWT) is an adjunctive treatment that uses constant negative pressure suction to facilitate healing. The utility of this treatment modality on vascular operations for critical limb-threatening ischemia (CLTI) has yet to be elucidated. This study compares the incidence of postoperative wound complications between the Prevena Incision Management System, a type of iNPWT, and standard wound dressings for vascular patients who also underwent plastic surgery closure of groin incisions for CLTI. We performed a retrospective cohort study of 40 patients with CLTI who underwent 53 open vascular surgeries with subsequent sartorius muscle flap closure. Patient demographics, intraoperative details, and wound complications were measured from 2015 to 2018 at the University of California San Francisco. Two cohorts were generated based on the modality of postoperative wound management and compared on wound healing outcomes. Of the 53 groin incisions, 29 were managed with standard dressings, and 24 received iNPWT. Patient demographics, comorbidities, and operative characteristics were similar between the 2 groups. Patients who received iNPWT had a significantly lower rate of infection (8.33% vs 31.0%, P = 0.04) and dehiscence (0% vs 41.3%, P < 0.01). Furthermore, the iNPWT group had a significantly lower rate of reoperation (0% vs 17.2%, P = 0.03) for wound complications within 30 days compared with the control group and a moderately reduced rate of readmission (4.17% vs 20.7%, P = 0.08). Rates of infection, reoperation, and dehiscence were significantly reduced in patients whose groin incisions were managed with iNPWT compared with standard wound care. Readmission rates were also decreased, but this difference was not statistically significant. Our results suggest that implementing iNPWT for the management of groin incisions, particularly in patients undergoing vascular operations for CLTI, may significantly improve clinical outcomes.

Peripheral Arterial Disease and the Diabetic Foot Syndrome: Neuropathy Makes the Difference! A Narrative Review.

Background: In vascular medicine, peripheral arterial disease (PAD) and diabetic foot syndrome (DFS) are often considered synonymous with respect to the need for revascularization. In PAD patients, clinical symptoms reflect the degree of atherosclerotic disease, since peripheral innervation, including pain sensation, is not usually compromised. In DFS patients, however, symptoms of relevant foot ischemia are often absent and progression of ischemia goes unnoticed owing to diabetic polyneuropathy, the loss of nociception being the main trigger for foot ulcers. This review analyzes the fundamental differences between PAD and DFS against the background of polyneuropathy. Methods: The literature research for the 2014 revision of the German evidence-based S3-PAD-guidelines was extended to 2023. Results: Vascular examination is imperative for both, PAD and DFS. Stage-dependent revascularization is of utmost importance in PAD patients, especially those suffering from critical limb-threatening ischemia (CLTI). Successful therapy of DFS goes further, including infection and metabolic control, wound management, offloading the foot and lifelong prophylaxis in the course of a multidisciplinary treatment concept. Revascularization is not needed in all cases of DFS. Conclusions: There are fundamental differences between PAD and DFS with respect to pathophysiology, the anatomical distribution of arterial occlusive processes, the clinical symptoms, the value of diagnostic tools such as the ankle-brachial index, and classification. Also, therapeutic concepts differ substantially between the two patient populations.

Acute and Mid-Term Results of Atherectomy in Femoropopliteal Lesions.

The femoropopliteal arteries are commonly affected by atherosclerotic lesions. The use of atherectomy may increase the benefit of definitive therapy, such as drug-coated balloon (DCB) angioplasty. To analyze the 2-year safety and efficacy of atherectomy in general and stratified by directional atherectomy (DA) and front-cutting atherectomy (FA) for the treatment of atherosclerotic lesions of the femoropopliteal arteries. A retrospective analysis was performed including patients who underwent vessel preparation with atherectomy. The primary endpoint was the 2-year incidence of target lesion revascularization (TLR). Secondary endpoints included primary patency, changes in ankle-brachial index (ABI) and Rutherford-Becker class (RBC), and amputation rate up to 2 years. Nine hundred and fifty-five patients (37.8% female; mean age: 69.7±9.6 years) were included in this analysis. Eight hundred and twenty-one patients (86%) were claudicants, 134 patients (14%) had critical limb-threatening ischemia. Six hundred and forty-four lesions (67.4%) were in a native artery and 145 lesions (15.2%) were in-stent restenoses. In 166 patients (17.4%), atherectomy was performed in native and in-stent segments. Eight hundred and thirty-seven patients were treated with DA and 118 patients with FA. Five-hundred and seventy-four procedures (60.1%) were followed by DCB angioplasty, provisional stent rate was 20% overall. One hundred and fifty-four procedure-related adverse events (16.1%) were documented, four complications (0.4%) required surgical intervention. At 2 years, 279 patients (34.3%) required TLR. After DA, TLR rates were 9%, 19.5%, and 32.2% at 6, 12, and 24 months, respectively, and 14.2%, 29.4%, and 49%, at 6, 12, and 24 months after FA. After DA, primary patency rates were 75.9%, 57.4%, and 40.3% at 6, 12, and 24 months, respectively, and 64.9%, 44.8%, and 26%, at 6, 12, and 24 months, respectively, after FA. Mean ABI and mean RBC improved significantly during follow-up (p<0.001), 17 patients required amputation, 13 minor (1.6%) and four major (0.5%). Regression analysis shows that more calcified lesions are more likely to have a TLR. Compared with a vessel diameter of 4 mm or smaller, larger diameters are associated with fewer TLRs. In this retrospective analysis, atherectomy of femoropopliteal lesions shows satisfactory mid-term results. German Clinical Trials Register: DRKS00031245. The results of this analysis could influence the daily practice of the interventionalists. A combination of atherectomy as vessel preparation followed by drug coated balloon angioplasty appears to be promising, but would need to be investigated in randomised trials.

Accuracy of maximal acceleration time of pedal arteries to diagnose critical limb-threatening ischemia.

Maximal acceleration time of distal arteries of the foot (ATmax) is correlated to ankle-brachial index (ABI) and toe-brachial index (TBI), and seems very promising in diagnosing severe peripheral artery disease (PAD) and especially critical limb-threatening ischemia (CLTI). Our goal was to confirm the cut-off value of 215 ms to predict a toe pressure (TP) ⩽ 30 mmHg. A 4-month retrospective study was conducted on patients addressed for suspicion of PAD. Demographic data, ABI, TBI, and Doppler ultrasound scanning parameters of the dorsal pedis and lateral plantar arteries (DPA and LPA) were recorded. A total of 137 patients with 258 lower limbs were included. ATmax was highly correlated to TBI (r = -0.89, p < 0.001). With the cut-off value of 215 ms, ATmax was effective to diagnose TP ⩽ 30 mmHg with a sensitivity of 93% [95% CI 77-99], a specificity of 96% [95% CI 92-98], a positive predictive value of 73% [95% CI 56-86], a negative predictive value of 99% [95% CI 97-100], and an area under the receiver operating characteristics curve of 0.99 [95% CI 0.98-1.00]. ATmax also showed promising results to rule out PAD in healthy patients. ATmax is a reliable diagnostic tool to diagnose low TP and could be a new easily performed hemodynamic criterion for diagnosis of CLTI.

Omniflow® II biosynthetic graft offers acceptable early and mid-term outcomes in redo surgery in patients with critical limb-threatening ischemia with no available autologous vein material.

In this study, the early and mid-term outcomes of Omniflow® II (LeMaitre Vascular, Inc., Burlington, MA, USA) biosynthetic graft in redo surgery in patients with critical limb-threatening ischemia (CLTI) with no available autologous vein material were investigated with the aim to compare the outcomes obtained in "de novo" surgery versus redo surgery. From January 2018 until December 2022, data of CLTI patients from 18 centers in Italy with no autologous vein material underwent infrainguinal bypass with Omniflow® II biosynthetic graft were collected. Thirty-day outcome measures including intraoperative technical success, major morbidity, mortality, and graft patency were assessed and compared. At two-year follow-up, estimated outcomes of survival, primary patency, primary assisted patency, secondary patency, freedom from reintervention, and amputation-free survival were analyzed using Kaplan-Meier curves and compared between groups using the log-rank test. In the study period 119 CLTI patients had an infrainguinal bypass with Omniflow® II biosynthetic graft. Seventy-seven patients (64.7%) underwent bypass as "de novo" treatment (group de novo), whilst in the remaining 42 patients (35.3%) the procedure was performed as redo surgery due to occlusion and/or infection of a previous bypass graft (group redo). Two groups were homogeneous in terms of demographic, clinical, and morphological data. In group redo explantation of an infected prosthetic graft was needed in 4 cases (9.5%). Intraoperative technical success was achieved in all cases in both groups. At 30 days, the overall patency rate did not differ between the two groups (69/77, 89.6%, group de novo vs. 35/42, 83.3%, group redo; P=0.24), whilst in group redo limb loss was higher with a statistically significant different 30-day major amputation rate between the two groups (11.9% group redo vs. 1.3% group de novo; P<0.001). Overall median duration of follow-up was eight months (IQR 6-13). At two-year follow-up there were no differences between the two groups in terms of survival (67.7% group de novo vs. 55.8% group redo, P=0.53), primary patency (34.4% group de novo vs. 26.8% group redo, P=0.25), primary assisted patency (43.6% group de novo vs. 28.8% group redo, P=0.12), freedom from reintervention (64.1% group de novo vs. 68.8% group redo, P=0.98), and amputation-free survival (67.8% group de novo vs. 60% group redo, P=0.12). Secondary patency was significantly higher in group de novo (53.7% vs. 32.3%, P=0.05). During the follow-up, the overall rates of graft infection and aneurysmal degeneration were 3.4%, and 0.8%, respectively. Nevertheless, poorer early outcomes in terms of limb salvage, Omniflow® II biosynthetic graft offers acceptable ywo-year outcomes in redo surgery in CLTI patients with no available autologous vein material. Further studies with larger population sizes are needed to validate these outcomes.

Endovascular recanalization of infra-popliteal TASC C and TASC D lesions in patients with critical limb-threatening ischemia: a single-center experience.

The present study aims to (1) assess the technical success and limb salvage rates of endovascular therapy in patients with critical limb-threatening ischemia (CLTI) and infra-popliteal Trans-Atlantic Inter-Society Consensus (TASC) C/D lesions according to the updated 2015 TASC II classification and (2) to present our institutional experience. A single-center retrospective study was conducted on patients with TASC C/D CLTI who underwent endovascular treatment between 2012 and 2017. The follow-up protocol consisted of Doppler ultrasound conduction every 3 months for the first year unless patients showed symptoms of CLTI. Patients with at least 1 year of follow-up data were included in the study, and if applicable their 3-year results were evaluated in terms of primary patency, absence of amputation, amputation-free survival, and overall survival. A total of 248 patients and 287 limbs (238 TASC D lesions and 49 TASC C lesions) were treated via infra-popliteal percutaneous transluminal angioplasty. The overall technical success was 87%, the primary patency rate was 41.5% in the first year, and the freedom from amputation rates were 80.8% in 1 year and 67.7% in 3 years. In patients with infra-popliteal arterial occlusive diseases, endovascular treatment methods demonstrate a high rate of technical success and favorable outcomes in limb preservation.

Predictors of major adverse lower limb events in patients with tissue loss secondary to critical limb-threatening ischemia

BackgroundChronic limb-threatening ischemia (CLTI) is the end-stage of peripheral arterial disease (PAD) posing a high risk for limb loss and mortality. This study aims to evaluate and list possible predictors of major adverse limb events (MALEs) in CLTI patients with tissue loss. MethodsThis retrospective study included all Rutherford-Becker stage 5 or 6 patients who required foot debridement and revascularization in our department from January 2016 to December 2018. The limbs were classified according to the TASC II, GLASS and WiFI grading systems. The primary composite outcome was MALEs at 2 years. The secondary outcomes included all-cause mortality, primary patency, freedom from reintervention, and major amputation. Kaplan-Meier estimates were used to determine the event rates, and Cox proportional hazards model with the index MALE as a time-dependent covariate was used to search for MALEs predictors. ResultsOf 241 included patients, 19 underwent open surgeries (7.9 %) 207 had endovascular interventions (85.9 %) and 15 required a hybrid approach (6.2 %). On univariate analysis, patients who experienced MALEs (n = 111) more often required hemodialysis (25 vs 15; p = .02), presented with more complex lesions (TASC D on femoropopliteal (p = .05) or below the knee (BTK) arteries (p = .006) with increasing infra-inguinal GLASS Stage (p < .0001)), a history of index limb open (p = .009) or endovascular (p = .049) revascularization, an occluded tibial artery (p = .002 for the posterior tibial and p = .052 for the anterior tibial), or a “desert foot” (p = .02). The CRP level was also higher at admission (p = .001). Technical success of BTK revascularization significantly reduced MALEs (p < .0001) along with the number of patent BTK vessels (p = .0007). Independent predictors of MALEs included hemodialysis (HR = 2.00; 95%CI: 1.14 to 3.39), pulsatile arterial pressure (HR = 1.01; 95%CI: 1.00 to 1.03) and the infra-inguinal GLASS Stage (HR = 2.50; 95%CI: 1.17 to 5.82). We could not correlate our results with the WiFI scores for amputation risk and revascularization benefit. ConclusionFor patients with CLTI at the stage of trophic disorders, with or without a history of index limb revascularization, the GLASS successfully predicted MALEs. Hemodialysis and high pulsatile arterial pressure increased the risk of MALEs. The WiFI score did not demonstrate its interest in this subgroup of patients.

Induced Pluripotent Stem Cell-Derived Mesenchymal Stromal Cells Promote Muscle Regeneration in a Diabetic Mouse Model of Critical Limb Threatening Ischemia

Critical limb threatening ischemia (CLTI), the end stage of peripheral arterial disease (PAD), is diagnosed in 500,000 patients each year, often results in amputation, and has a ~50% 5-year mortality rate. Diabetic CLTI patients experience especially high morbidity and mortality, and no effective non-surgical therapy exists for this population. Our Phase II MOBILE trial demonstrated that autologous bone marrow nucleated cells were unable to prevent amputations in diabetic patients; however, data from a Phase I trial shows that allogeneic bone marrow-derived mesenchymal stromal cells (BMD-MSC) stimulated angiogenesis in ischemic muscle, including diabetics. While allogeneic MSC may be an effective cell preparation to treat diabetic CLTI, passaging-related cell senescence prevents generation of sufficient cell numbers for therapeutic use. The development of induced pluripotent stem cell (iPSC)-derived MSC overcomes cell senescence issues and offers the possibility of genetic modifications to enhance cell function. The current study was designed to determine potential mechanisms by which iPSC-MSC stimulate muscle regeneration in a rodent CLTI model.&#x0D; The CLTI mouse model was created by ligation/excision of the femoral artery in male polygenic diabetic TallyHo mice. Mice with intramuscular administration of iPSC-MSC displayed positive indicators of muscle regeneration compared to vehicle control mice. Real-time PCR performed with gastrocnemius muscle obtained 7- or 30-days post iPSC-MSC injection showed an increase in mRNA expression for MyH3, MyoD1, Mrc1, FoxP3, and VEGF-A vs. vehicle treated muscle, indicating promotion of muscle regeneration, M2-biased macrophage expression, T regulatory cell (Treg) expansion, and vascular proliferation. Downregulation of the NADPHoxidase subunit p47phox indicated a decrease in oxidative stress in the treated mice. The results are consistent with iPSC-MSC promotion of muscle regeneration via a Treg mediated stimulation of the M1-M2 macrophage phenotypic shift. Thus, human iPSC-MSC could be an effective treatment to stimulate muscle regeneration and ameliorate CLTI in diabetic patients.

Neuropathy Screening for Patients with Peripheral Vascular Disease Helps to Identify Those at an Increased Risk of Amputation, Revascularization, and Death

Peripheral neuropathy is associated with amputation risk among patients with diabetes mellitus and chronic limb-threatening ischemia (CLTI). Detection of peripheral neuropathy may help identify those who are at an increased risk, but the predictive ability of the screening tool used in patients with peripheral arterial disease (PAD) needs to be more clearly defined. Patients referred to vascular surgery clinic for PAD were recruited from a single center. Exclusion criteria were a documented history of neuropathy or prior lower limb amputation. Screening utilized the Michigan Neuropathy Screening Instrument (MNSI). Scores >2.5 were considered abnormal and scores >4 were considered positive for peripheral neuropathy. Limb-specific outcomes of amputation and revascularization as well as a composite outcome including death were modeled using time to event analysis. 86 patients were recruited. Mean age was 67±10.2years, 30% were women, 24% were black. Mean ankle-brachial index was 0.74±0.3. PAD symptoms at initial evaluation were claudication in 52% of patients and CLTI in 38% of patients. Neuropathy was present in 20% of the cohort with a significantly higher proportion in diabetics (34% vs. 3%; P=0.0009). Neuropathy was more common in patients with CLTI compared to claudicants (36% vs. 9%; P=0.011). Forty patients (47%) reached the composite outcome of amputation, revascularization, or death with a median time to event of 16months. Abnormal MNSI examination was significantly associated with the increased risk of the composite outcome (hazard ratio=3.19; P 0.0005). A significant proportion of patients presenting to vascular specialists for PAD have undiagnosed neuropathy. Patients with PAD and neuropathy have an increased risk of amputation, revascularization, and death. Expanding neuropathy screening in vascular surgery clinic visits may help to identify patients at higher risk.

Recanalization of Chronic Femoropopliteal Total Occlusions after Failed Anterograde Attempt: Use of an Intravascular Ultrasound–Guided Re-entry Catheter versus the Bidirectional Approach

PurposeTo analyze the feasibility and effectiveness of the use of an intravascular ultrasound (IVUS)–guided re-entry catheter (IGRC) for femoropopliteal chronic total occlusions (FP-CTOs) after a failed anterograde approach compared with the bidirectional approach without the IGRC. Materials and MethodsBetween June 2019 and December 2022, an IGRC (Pioneer Plus; Philips Volcano, San Diego, California) was used in 52 patients after failure of conventional recanalization techniques (Group A). In the same period, 48 patients who were also eligible for IGRC use were treated without IGRC using the bidirectional approach (Group B). In Groups A and B, 12 (23.1%) and 3 (6.2%) patients experienced claudication, and 40 (76.9%) and 45 (93.7%) patients experienced critical limb-threatening ischemia, respectively. Clinical and procedural records, angiographic imaging findings, and follow-up data were collected, analyzed, and reviewed. ResultsTechnical success was achieved in 49 (94.2%) patients in Group A and 44 (91.7%) patients in Group B (P = .616). Use of the IGRC was associated with a reduction of procedural time (120 vs 133 minutes; P < .001), radiation exposure (47 vs 59 Gy cm2; P < .001), iodinated contrast medium use (98 vs 138 mL; P = .028), and intraprocedural discomfort (numerical rating scale score, 4 vs 6; P < .001). ConclusionsUse of the IGRC was equivalently successful for FP-CTO recanalization compared with the use of the bidirectional approach, but it reduced radiation exposure, iodinated contrast medium used, patient discomfort, and procedural time. These advantages suggest that IGRC could be favored as the next-choice option for FP-CTOs after failure of anterograde recanalization.

Anatomic patterns in claudicants who fail supervised exercise therapy

ObjectivePatients with intermittent claudication (IC) from peripheral arterial disease (PAD) have significant improvement with supervised exercise therapy (SET). However, many patients have progressive disease that will ultimately require revascularization. We sought to determine whether the anatomic patterns of PAD were associated with response to SET. MethodsWe prospectively enrolled patients with IC at the West Haven, Connecticut Veterans Health Administration between June 2019 and June 2022. Patients were classified based on the level of their arterial disease with >50% obstruction. SET failure was defined as progressive symptoms or development of critical limb-threatening ischemia (CLTI) requiring revascularization. ResultsThirty-eight patients with PAD were included. Thirteen patients (34.2%) had significant common femoral artery (CFA) disease, and 25 (65.8%) had non-CFA disease. Over a median follow-up of 1407 days, 11 patients (84.6%) with CFA disease failed SET as compared with three patients (12.0%) with non-CFA disease (P < .001). Patients with CFA disease were more likely to develop CLTI (46.2% vs 4.0%; P = .001) and have persistent symptoms (38.5% vs 8.0%; P = .02). Patients with CFA disease had significantly lower post-SET ankle-brachial index (0.58 ± 0.14 vs 0.77 ± 0.19; P = .03). In multivariate analysis, the only variable associated with SET failure was CFA disease location (odds ratio, 68.75; 95% confidence interval, 5.05-936.44; P = .001). ConclusionsPatients with IC from high-grade CFA atherosclerosis are overwhelmingly likely to fail SET, potentially identifying a subset of patients who benefit from upfront revascularization.

Insufficient arterial driving pressure turns hypoxic microvascular remodeling into a catastrophe

Abstract The tissue microvasculature is known to remodel in response to ischemia. However, the benefit or harm of this process is not completely understood and may limit also the potential of taking control of ischemic diseases that remain the leading cause of death worldwide. In a series of clinical and preclinical studies, we have thus dissected the biological relevance and the pathomechanistic role of hypoxic microvascular remodeling in critical limb threatening ischemia (CLTI). High-resolution contrast enhanced ultrasound was used in 50 patients with severe CLTI scheduled for immediate revascularization to study ischemic muscle microvascular blood flow. Immunohistological analyses were performed for amputation muscle samples from a set of 40 CLTI patients to analyze microvascular changes with respect to the level of myofiber atrophy. Furthermore, the amputation muscle samples were used to find 3 paired samples from 20 patients representing microvascular transformation along worsening of ischemic muscle damage, and used for RNA sequencing to analyze mechanisms of microvascular transformation. Additionally, animal models for acute ischemia in C57Bl-mice (n=42) and hypercholesterolemic LDLR-/-ApoB100/100 mice (n=61) and chronic CLTI-like ischemia model in cholesterol-fed NZW rabbits (n=24) with AdVEGF-A or AdLacZ control gene transfer were employed to study: 1) the natural course of microvascular changes leading to efficient muscle regeneration; 2) the effect of reduced arterial driving pressure on muscle regeneration; and 3) the effect of reduced arterial driving pressure and microvascular transformation on muscle regeneration, respectively. Decreased capillary transit time (P&amp;lt;0.01) and a gradual arterialization of capillaries along worsening of ischemic tissue damage (P&amp;lt;0.001) were observed in CLTI muscle. CLTI muscle RNA sequencing further suggested that the capillary arterialization process is an orchestration of different growth factors, cell types and even physical forces in the hypoxic muscle. Furthermore, animal models of acute and chronic limb ischemia display post-ischemic capillary enlargement (P&amp;lt;0.05) as a primary microvascular modification that facilitates collateral maturation but under decreased arterial driving pressure can turn from a good intention to aggravating ischemic damage. These results depict a critical role for the microvasculature in determining ischemic muscle outcome after an initial arterial occlusion in CLTI. Hypoxic microvascular remodeling, according to this data, initially has a good purpose but can also cause harm given enough time and the wrong environment. Moreover, these results offer understanding to the differential natural recoveries of experimental animals and human patients from an ischemic exposure – information that is essential for designing better treatments for ischemic diseases.

Abstract 18185: A Multicenter Prospective Trial of Therapeutic Angiogenesis Using Bone Marrow-Derived Mononuclear for Patients With Critical Limb-Threatening Ischemia Caused by Thromboangiitis Obliterans

Background: Thromboangiitis obliterans (TAO) can develop critical limb-threatening ischemia (CLTI). Despite conventional treatments, such as smoking cessation or revascularization, young patients require limb amputation. Therapeutic angiogenesis using bone marrow-derived mononuclear cell (BM-MNC) implantation has demonstrated long-term efficacy and safety in patients with CLTI, particularly those with TAO. To expand BM-MNC implantation in clinical practice, further evidence is required in CLTI patients with TAO. We aimed to determine the efficacy of BM-MNC implantation in a prospective trial. Methods: This multicenter, prospective, interventional trial was performed under an advanced medical care program. We enrolled 22 patients with CLTI and skin perfusion pressure (SPP) &lt;30 mmHg; they underwent BM-MNC implantation within 28 days (Figure.1). The follow-up period was 180 days, and the primary endpoint was an improvement in the SPP value in the affected target limb 180 days after the implantation. One patient dropped out from the follow-up. Results: The mean age was 47.6 years (male: 90.5%, Fontaine classification IV: 57.1%). The SPP value significantly improved on day 180 (p&lt;0.001) (Figure. 2). The secondary endpoints, i.e., numerical rating scale scores and transcutaneous oxygen pressure values significantly improved within day 180. The 3-year major amputation-free and overall survival probability in the safety analysis set were 95.5% and 89.5%, respectively (Figure. 3). No severe adverse events occurred. Conclusions: We believe that the BM-MNC implantation will likely become a feasible and safe therapy for CLTI patients caused by TAO.