Peripheral Arterial Disease Patients Research Articles

Diversity in clinical trial inclusion for peripheral artery disease lower extremity endovascular interventions: a systematic review protocol.

Aim: This review provides a study protocol for a systematic review of peripheral artery disease (PAD) clinical trials to examine the eligibility criteria, demographic representation, and enrollment strategies among PAD patients undergoing lower extremity (LE) endovascular interventions. Methods: This systematic review will be conducted according to the Cochrane Collaboration methodology for systematic reviews and following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P). Eligible studies will include randomized controlled trials (RCTs) between January 2012 and December 2022. The primary outcome will be a description and summary of the frequency of the reporting of demographic characteristics. The feasibility of a meta-analysis or meta-regression will be explored, but if determined to be infeasible, the Synthesis Without Meta-analysis (SWiM) reporting guideline will be followed for the reporting of findings. Discussion: The findings may help to quantify existing inequities in clinical trial participation that may be addressed through optimizing enrollment strategies for future PAD trials. Systematic review registration: PROSPERO (CRD42022378304).

The impact of Covid-19 on mortality and clinical characteristics in hospitalized patients with peripheral artery disease in the year 2020

Abstract Background The Covid-19 pandemic developed its full destructive capacity and caused over 6.6 million confirmed deaths worldwide in the year 2020. This retrospective study aimed to examine the effects of Covid-19 on the mortality and clinical characteristics of peripheral artery disease (PAD) patients because these chronically ill patients are at risk for arterial embolic vascular complications and a fatal outcome. Methods and results From a German nationwide registry of 2020 all patients hospitalized with PAD (n=173.075) were compared in four different groups. The first group had no additional diabetes mellitus type 2 or Covid-19 (n=110.531), the second diabetes mellitus but no Covid-19 (n=59.991), the third diabetes mellitus and Covid-19 (n=1497) and the fourth no diabetes mellitus but Covid-19 (n=1056). Mortality rates in all PAD patients without Covid-19 were low and ranging between 1.1-3.6%, depending on PAD classification. However, PAD patients with Covid-19 had significantly higher mortality rates of 11.1-12.6%. Clinical characteristics and the Charlson- comorbidity index surprisingly revealed that PAD patients with Covid-19 but without diabetes mellitus presented more complications such as higher rates of stroke (1.4%), cardiogenic shock (3.3%), chronic kidney failure with GFR < 15 ml/min (10.5%) and prolonged ventilation time >48 hours (4.4%). Conclusion Covid-19 massively increased death rates in PAD patients in the year 2020. Neither disease severity of different stages of PAD nor additional diabetes mellitus had an effect on in-hospital mortality. One explanation of this finding might be that the risk for arterial embolism increases after a Covid-19 infection and thus leads to higher mortality rates in PAD patients, who are in danger for vascular/embolic complications. Our study reveals the importance of preventing the spread of Covid-19 disease, especially in the case of patients with atherosclerotic diseases.

Underutilization of guideline-recommended therapy in patients 80 years and older with peripheral artery diseases

Abstract Background Ageing is a major cardiovascular risk factor with detrimental pathophysiological changes that culminate in a high atherosclerotic burden. Peripheral artery disease (PAD) is a major manifestation of atherosclerosis with high mortality. Guideline-recommended treatment is essential, however implementation is inadequate. With an ageing society, age-related inequalities are important and have not been elucidated in a high-risk PAD population on a nation-wide scale. We sought to analyse the outpatient treatment structures and guideline adherence in treatment of PAD patients older than 80 year of age. Purpose Aim of the study was to identify age-based inequalities in outpatient treatment care and pharmacotherapy in PAD patients. Methods We analyzed age-related differences in prevalence, pharmacotherapy (statins, antiplatelets) and treatment by specialized outpatient care (angiology, vascular surgery, internal medicine, cardiology) in 17,633,970 patients with PAD and statutorily insurance presenting to outpatient care facilities in Germany between 2009 and 2018. The study is based on ambulatory claims data of the panel doctors’ services according to §295 SGB V and drug prescription data according to §300 SGB V, comprising 70.1 million patients per year. Diagnosis of PAD was defined upon medical diagnoses of PAD ICD. Statistical analysis was performed with chi-squared test for trend and two-way Anova. Results Of 17,633,970 PAD patients included, 28% were older than 80 years. PAD prevalence increased between 2008 and 2019 (1.85% vs 3.14%), with the proportion of the elderly increasing by a third (24.4% vs 31.2%). Octogenarians were undertreated regarding guideline-recommended statin pharmacotherapy compared to younger patients throughout the observed 10 year time frame (statins 2016: 46.5% vs 52.4%; antiplatelets 2016 30.6% vs 29.3%; p < 0.05). Furthermore, octogenarians received less specialized outpatient care (angiology: 6.4% vs 9.5%, vascular surgery: 8.1% vs 11.8%, cardiology: 25.2% vs 29.2%, p < 0.05). Conclusions Our results demonstrate that age-related differences in pharmacotherapy and specialized outpatient care of PAD patients are evident. While overall guideline-recommended outpatient treatment is low, patients 80 years and older are less likely to receive both, leaving age-related health inequalities a challenge of our future.

Colchicine for cardiovacular risk reduction in lower extremity peripheral artery disease

Abstract Introduction Although recent evidence from randomized trials suggests colchicine can reduce major adverse cardiovascular events (MACE) in patients with coronary artery disease, its effect in lower extremity peripheral artery disease (PAD) is not known.1,2 To make inferences about the effects of colchicine in PAD, we leveraged the variable prescribing practice of adding colchicine versus a non-steroidal anti-inflammatory (NSAID) to urate lowering therapy in patients with gout and PAD. Purpose Estimate the effect of colchicine therapy initiation on adverse cardiovascular and limb events in a real-world sample of high-risk patients with PAD and gout. Methods A pragmatic open-label target trial comparing colchicine initiators (treatment group) to NSAID initiators (control group) was emulated in PAD patients taking either drug in conjunction with initiation of urate lowering therapy. Patients were enrolled between July 2007 and December 2019 using electronic health records from a multi-hospital academic medical system linked to Medicare claims data. Patients with contraindications to colchicine or NSAIDs (e.g., severe kidney disease, hepatic failure) were excluded. Inverse probability of treatment weighting was used to create a pseudopopulation balanced with respect to risk factors for the outcomes. The primary outcome was a 5-year composite of major adverse limb events (MALE), MACE, and all-cause mortality. Secondary outcomes included MALE and death, MACE and death, and individual components of the primary outcome accounting for the competing event of death. Risks were estimated with the Kaplan-Meier estimator for the composite outcomes and the Aalen-Johansen estimator for the competing event outcomes. Percentile based 95% confidence intervals were generated using nonparametric bootstrapping. Results A total of 1,786 patients were enrolled; mean age was 77 years (SD 7), 33% were female, and 9% were non-white race (Table). Maximum absolute standardized mean difference in relevant covariates was 23% prior to weighting and 0.8% after weighting, indicating covariate balance. The risk of the primary composite outcome of MALE, MACE, and death at 5 years was 58% (95% CI 55%, 61%) in the colchicine group and 60% (95% CI 56%, 64%) in the control group, with a risk difference of -2% (-8%, 4%) and risk ratio of 0.96 (0.89, 1.04; Figure). Similar findings were noted in the secondary composite outcomes (Figure). In the analysis accounting for the competing risk of death, the cause-specific risk of MALE (9% colchicine vs. 9% control) and MACE (24% colchicine vs. 26% control) alone were similar at 5 years. Conclusions In a real-world sample of high-risk patients with PAD and gout, colchicine did not appear to reduce the risk of adverse cardiovascular or limb events. The cardiovascular benefits of colchicine in older populations with PAD and advanced systematic atherosclerosis remain uncertain.Table.Patient characteristics.Figure.Weighted Kaplan-Meier estimates.

Reduction in the risk of major adverse limb events with ezetimibe versus placebo in addition to statin therapy: insights from the IMPROVE IT trial

Abstract Background/Introduction Patients with peripheral artery disease (PAD) are at risk of developing progressive symptoms leading to revascularization as well as major adverse limb events such as critical limb ischemia and amputation. Recently, two trials of PCSK9 inhibitors, which lower both LDL-C and Lp(a) have demonstrated reductions in MALE and peripheral revascularization. Whether this benefit is present for other LDL-C lowering therapies has not been well described. Purpose To evaluate whether LDL-C lowering with ezetimibe reduces the risk of adverse limb events. Methods IMPROVE-IT randomized 18,144 patients with acute coronary syndrome (ACS), including 1,005 with PAD, to ezetimibe or placebo on top of statin and followed for a median of 6 years. Two vascular specialists blinded to treatment allocation independently reviewed all adverse events to categorize limb outcomes including critical limb ischemia (CLI), and related amputation as well as progressive symptoms leading to lower extremity revascularization (worsening PAD). Total limb outcomes over follow up were compared by treatment groups using negative binomial regression and relative risks (RR) are presented. Results A total of 397 patients had worsening symptoms (in 346 PAD patients) and 43 developed CLI (in 36 patients) during follow up. The risk of total PAD events (CLI or worsening symptoms) was lower with ezetimibe versus placebo (RR 0.77, 95% CI 0.62 – 0.96, p=0.018) with a consistent trend for both components (Figure Panel A). When evaluating the relationship of achieved LDL-C at 1-month post-randomization and the risk of first PAD event, there appeared to a linear relationship extending to an LDL-C less than 25 mg/dL (Figure Panel B). Conclusion Further lowering of LDL-C with ezetimibe on top of statin therapy in patients with ACS was associated with a lower risk of adverse limb events over long-term follow up including CLI and progressive disease leading to revascularization. These data support the importance of intensive lipid lowering therapies in improving limb outcomes in patients with atherosclerotic vascular disease. In addition, these data support LDL-C as a treatment target for optimizing outcomes in patients with peripheral artery disease.Figure Panel AFigure Panel B

Vascular effects and benefits through Helical stent implantation vs. conventional stenting: Methodology and initial Results of The MIMICS FLOW investigator-initiated randomized controlled trial

Abstract Aims Endovascular treatment is the primary revascularization strategy for symptomatic peripheral artery disease (PAD), which not only restores tissue perfusion but also affects local lower limb arterial endothelial function. Endothelial dysfunction is the pathophysiologic principle involved in the progression of atherosclerosis and is a prognostically relevant cardiovascular biomarker. A helical stent with a unique 3D helical geometry promotes laminar swirling blood flow elevating wall sheer stress, providing superior hemodynamic advantages and excellent clinical performance as compared to conventional stenting. The potential impact on endothelial homeostasis and the detailed mechanisms following a biomimetic or conventional stent are unknown. To this aim we now determined the effect of the Biomimics or a conventional stent on endothelial and vascular function in symptomatic PAD. Methods The MIMICS-FLOW is an investigator-initiated single-blind, randomized controlled trial (NCT05447052). The influence of novel stent-platforms with improved hemodynamic capabilities with respect to vasomotion of the vessel wall, vascular function and vascular compliance was measured by flow-mediated dilation (FMD) and arterial stiffness indices. Vascular function was determined in 70 PAD patients, Rutherford 2, 3 and 4 randomized to a helical stent and the conventional straight nitinol stent before and after lower limb intervention with a one-month follow-up in the nonstenotic segment of the proximal SFA. Perfusion indices, TLR rate and primary patency were assessed. Results The methodology and initial results regarding endothelial function after 1 month will be presented at ESC. In brief, 70 Patients aged 67 years were 1:1 randomized to each group prior to stent implantation in the SFA. Rutherford and PACSS class and target lesion locations were balanced between groups. One patient in the helical and 2 patients in the Straight group required a reintervention. A higher improvement in SFA FMD was observed in the helical group as compared to conventional stenting (p<0.05). Importantly, this effect was mirrored also by a greater increase in brachial FMD in the helical vs. conventional group (p<0.05). No impact was observed between groups regarding arterial or aortic stiffness. Conclusions Our RCT data provide evidence for an improved vascular function through swirling flow with superior hemodynamics following a helical stent implantation. These findings support the concept for a better mechanistic understanding to enhance endovascular treatment strategies in PAD.

Multimodal Prehabilitation for Peripheral Arterial Disease Patients with Intermittent Claudication—A Pilot Randomized Controlled Trial

To establish the feasibility and safety of multimodal prehabilitation (MP), and to obtain pilot data on the change in quality of life, functional walking capacity, and the need for surgery for a full-scale trial. Pilot randomized controlled trial that included patients older than 50years old suffering from moderate to severe intermittent claudication and who were candidates for endovascular revascularization (ER). Participants were excluded if they presented with ischemic rest pain, gangrene or ulceration of the index leg, significant lesions in the iliac vessels, planned surgical bypass, comorbidities in which exercise was contraindicated or if they were unable to speak English or French. Participants were randomized in a 1:1 ratio to 12weeks of MP or institutional standard of care (unsupervised walking advice). MP consisted of i)1 weekly supervised exercise session; ii) home-based exercise prescription; iii) nutritional counseling and supplementation; iv) smoking cessation therapy; and v) psychosocial support. Feasibility and safety were measured with recruitment and retention rates, as well as the occurrence of any adverse events. In addition, barriers to attend supervised sessions and compliance to each component were assessed. Change in functional walking capacity, health-related quality of life, and the rates of patients deciding not to undergo ER were collected and analyzed throughout the follow-up period of 12months. Of the 37 patients referred for eligibility, 27 (73%) accepted to participate in the trial and were randomized. Of the 27 patients included, 24 completed the 12-week program. Adherence to each prehabilitation component was 83% interquartile range [72,93] for supervised exercise, 90% [83,96] for home-based exercise and 69% [45,93] for nutritional sessions. Fifty percent of patients were referred for and underwent psychosocial intervention and 40% of the active smokers enrolled in the smoking cessation program. No adverse events were observed during the program. The 2 main barriers for not fully adhering to the intervention were excessive pain while performing the exercises and the difficulty to keep up with the prescribed exercises. A statistically significant mean change (standard deviation (SD)) was seen in the MP group versus standard of care for functional capacity, mean (SD) 6 Min Walk Test 60 (74) vs. -11 (40) meters P<0.05, and quality of life mean (SD) VascuQol 1.15 (0.54) vs. -0.3 (1.09) points P<0.05. There was no statistically significant difference between groups in the rates of patients deciding to undergo ER during the 1-year follow-up period. The results of this pilot trial demonstrate that MP is safe and feasible. A 12-week MP program seems to improve quality of life and functional walking capacity to a greater extent than unsupervised walking advice. There is a need for a large-scale trial to investigate the effectiveness of MP at improving quality of life and assessing its impact on the rates of patients deciding not to undergo or delay ER. The long-term functional and quality of life outcomes of the patients deciding to undergo ER after prehabilitation also need to be assessed.

Abstract 16428: Impact of Low-Dose Rivaroxaban Plus Aspirin on Myocardial Infarction in Patients With Peripheral Artery Disease With and Without Concomitant Coronary Artery Disease: Insights From VOYAGER PAD

Background: Patients with peripheral artery disease (PAD) are at heightened risk of major adverse cardiovascular events (MACE). In VOYAGER PAD, rivaroxaban 2.5 mg BID reduced ischemic risk in PAD patients after lower extremity revascularization (LER). Whether the benefits for MACE and in particular for Myocardial Infarction (MI) differ in those with and without clinically known coronary artery disease (CAD) has not been described. Hypothesis and Methods: VOYAGER PAD randomized patients with symptomatic PAD undergoing LER to rivaroxaban 2.5 mg BID plus aspirin versus aspirin alone. MACE was defined as composite of MI, ischemic stroke, or cardiovascular death. Subtypes of MI were adjudicated according to the Universal Definition. Comorbid CAD was a prespecified subgroup. Results: Of 6,564 symptomatic PAD randomized, 2,083 (32%) had documented CAD at baseline. The benefit of rivaroxaban plus aspirin was greater for MACE in those with vs without CAD (HR 0.79, 95% CI 0.62 - 1.00 vs HR 1.12, 95% CI 0.92 - 1.36; p-interaction 0.03). Similarly, MI reduction with rivaroxaban plus aspirin was greater for those with vs without CAD (HR 0.78, 95% CI 0.56 - 1.10 vs HR 0.96, 95% CI 0.69 - 1.34; p-interaction 0.39). Considering MI subtypes, the effect of rivaroxaban plus aspirin on type 1 MI was consistent in patients with CAD (HR 0.91, 95% CI 0.58 - 1.42) and without CAD (HR 0.74, 95% CI 0.74 - 1.11, p-interaction 0.50). However, a trend towards benefit of rivaroxaban plus aspirin was seen for Type 2 MI in those with CAD (HR 0.71, 95% CI 0.41 - 1.24) but not in patients without CAD (HR 1.66, 95% CI 0.89 - 3.09, p-interaction 0.0475, figure). Type 4 MI was infrequent regardless of CAD. Conclusions: Rivaroxaban plus aspirin had consistent effects in MACE for PAD and CAD patients undergoing LER. Our analysis of MI subtype suggests that events adjudicated as MI due to supply demand mismatch (Type 2) may have a thrombotic component and are lowered with rivaroxaban and aspirin in PAD and CAD patients undergoing LER.

Abstract 18385: Platelet Transcriptome in Type 2 Diabetes Provides Insight Into Peripheral Artery Disease and Cardiovascular Events

Background: Platelets are integral to atherothrombosis and peripheral artery disease (PAD), processes that are accelerated in diabetes. We evaluated the platelet transcriptome, generated a platelet RNA score, and investigated whether it could serve as a novel biomarker of PAD severity and major adverse cardiovascular events (MACE). Methods: We performed RNA sequencing on circulating platelet samples obtained from 133 patients enrolled in the platelet activity and cardiovascular events in PAD study. The transcriptome was (1) compared in PAD patients with Type 2 Diabetes (T2D) (n=73) vs without T2D (n=60), and (2) correlated with platelet aggregation responses to submaximal epinephrine (0.4uM). Using the overlap of transcripts identified by these approaches, we scored each sample based on a rank-based phenotypic metric (Singscore) to develop a T2D-specific platelet RNA score. This platelet score was compared in PAD patients with (vs without) critical limb ischemia (CLI), and PAD patients with (vs without) incident MACE (myocardial infarction, stroke, or death) after multivariable adjustment. Results: Overall, 384 transcripts were differentially expressed in PAD patients with vs without T2D (P&lt;0.01; 195 upregulated and 189 downregulated). Gene set enrichment analysis noted upregulation of pathways related to cell chemotaxis, acute inflammatory response, and platelet alpha granules in T2D. Among these 384 genes, 102 significantly correlated with platelet aggregation (P&lt;0.01) and were used to create a T2D platelet RNA score. To evaluate its clinical significance, this score was 3- times higher in PAD with (vs without) CLI (P=0.002). Further, after adjusting for age, sex, race, T2D, hypertension and coronary artery disease, the platelet score above (vs below) the median was associated with increased MACE (HR 2.8, 95% CI 1.4 to 5.6, P = 0.003). Conclusions: These findings demonstrate a unique platelet transcriptome in T2D that is associated with PAD severity and future risk of cardiovascular events. This work provides an important step toward the use of platelet RNA to unlock novel molecular mechanisms and inform future clinical outcomes.

Abstract 12634: Amplified P2x 3 Pathway Activity in IB4 Positive Muscle DRG Neurons and Exercise Pressor Reflex Regulation in Hindlimb Ischemia-Reperfusion

Background: Hindlimb ischemia-reperfusion (IR) represents one of the most prominent pathological conditions observed in peripheral artery disease (PAD). Arterial blood pressure response (BP) during exercise, partly driven by the exaggerated exercise pressor reflex (EPR), is associated with an elevated risk of cardiovascular events in PAD patients. However, the precise underlying mechanisms leading to this exaggerated BP response are poorly elucidated. The purinergic P2X 3 signaling pathway, which plays a key role in modifying the EPR, was the focus of the present study. Objectives: To examine the regulatory role of P2X 3 on the EPR in a rat model of hindlimb IR, which was induced by 6 hours’ ischemia followed by 18 hours’ reperfusion (referred to as IR rats). Results: We found that, in IR rats, there were: 1) upregulation of P2X 3 protein expression in the L4-6 dorsal root ganglion (DRG) (1.48±0.16 in IR rats/n=8 vs. 1.00±0.41 in sham rats/n=9; P&lt;0.05), which was localized in IB4 positive DRG neurons by the method of immunohistochemistry, 2) amplified P2X currents in isolated muscle DRG neurons (P2X transient currents: 1281.64±776.74 pA in IR rats/n=25, vs. 717.91±556.2 pA in sham rats/n=9, P&lt;0.05; and sustain currents: 466.94±168.68 pA in IR rats/n=11, vs. 271.49±200.90 pA in sham rats/n=8, P&lt;0.05); 3) amplification of P2X-mediated BP response (29±8 mmHg in IR rats/n=12 vs. 21±4 mmHg in sham rats/n=7; P&lt;0.05); and 4) alleviation of the exaggerated BP response induced by static muscle contraction (18±8 mmHg in IR +A317491/n=8, vs. 29±11 mmHg in IR/n=7, P&lt;0.05) and P2X-mediated BP response by α, β-me-ATP injection (15±4 mmHg in IR+A317491 /n=6 vs. 23±7 mmHg in IR/n=4, P&lt;0.05) following the inhibition of muscle afferents’ P2X 3 receptor by A-317491. We further verified that both A-317491 and siRNA knockdown of P2X 3 significantly decreased the activity of P2X currents in the isolated muscle DRG neurons (all P&lt;0.05 vs. their respective controls). Conclusion: With the above evidence from multiple approaches, we concluded that the P2X 3 signaling pathway activity is amplified following hindlimb IR via the enhancing expression and activity of P2X 3 receptors in IB4 positive muscle DRG afferents. This contributes to the exacerbated EPR responses in PAD.

Abstract 17363: Loss of Skeletal Muscle Bmal1 Impairs Limb Perfusion and Muscle Regeneration in a Mouse Model of Peripheral Arterial Disease

Introduction: Peripheral arterial disease (PAD) is a growing pathologic condition worldwide and leads to severe myopathy. Traditional risk factors for PAD, including diabetes, smoking, and advanced age, are associated with disrupted circadian clock function. However, the contribution of circadian disruption to PAD remains poorly understood. Hypothesis: This study aims to investigate the role of skeletal muscle clock in the severity of PAD. Methods: We performed femoral artery ligation (FAL) surgery in male adult-life inducible skeletal muscle-specific Bmal1 knockout ( Bmal1 musc ) (n = 6) and control mice (n = 5). We measured limb perfusion with laser doppler imaging weekly and assessed post-surgical angiogenesis with CD31/αSMA co-immunostaining and muscle recovery with hematoxylin and eosin (H&amp;E) staining and Laminin immunohistochemistry at 30 days post-surgery. We also performed RNA-sequencing, qPCR, and Western blotting assays to characterize the differentially expressed genes in both ligated and non-ligated hindlimb muscles. Results: Adult-life deletion of skeletal muscle Bmal1 reduced reperfusion recovery, with an average rate of only 50% by 22 days post-surgery in Bmal1 musc mice compared to approximately 80% in control mice. HIF1α target genes including the pro-angiogenic factor Vegfα were significantly downregulated in Bmal1 musc mice. Conversely, genes enriched in the anti-angiogenic TGF-β signaling pathways were up-regulated in Bmal1 musc mice. Myostatin, a myokine that inhibits muscle growth, was downregulated in Bmal1 musc muscles. H&amp;E staining and Laminin immunohistochemistry revealed significantly less but enlarged newly formed myofibers in the tibialis anterior muscle in Bmal1 musc mice. Conclusions: Skeletal muscle BMAL1 plays a critical role in determining the severity of ischemic muscle injury in a mouse model of PAD. Circadian dysfunction impairs hindlimb ischemia reperfusion, decreases the number of newly formed myofibers, and promotes the formation of enlarged regenerating myofibers, which is however previously reported to be associated with compromised muscle force production. Restore muscle circadian function could be a promising strategy to ameliorate myopathic severity in PAD patients.

Abstract 16108: Impact of Early Intervention on Quality of Life Outcomes in Peripheral Artery Disease Patients With Chronic Total Occlusion Lesions: Results From the PORTRAIT Registry

Background: Peripheral artery disease (PAD) is associated with functional impairment, decreased quality of life, and increased risk of cardiovascular events and mortality. Chronic total occlusion (CTO) lesions occur in up to 40% of PAD patients and pose a challenge for successful endovascular revascularization. We aim to evaluate the baseline characteristics, presentations, procedural outcomes, and quality of life (QOL) outcomes of CTO lesions in PAD compared to non-CTO lesions and the interaction with invasive therapy. Methods: The PORTRAIT registry is a prospective, multicenter, international study that enrolled patients with new or worsening claudication symptoms and an abnormal resting or post-exercise ankle brachial index. Patients with CTO lesions were compared to those without CTO lesions and divided into those who received early invasive treatment (revascularization within three months of enrollment) or noninvasive treatment with medical management. Quality of life outcomes were evaluated using the Peripheral Artery Questionnaire (PAQ) at baseline and during follow-up at 3, 6, and 12 months. Results: A total of 581 matched patients were identified, of which 39% had CTOs and 61% did not. Of the patients with CTOs, 31% underwent early invasive treatment and 69% were noninvasively managed. Patients with CTOs were more likely to present with higher Rutherford classification. The PAQ Summary Score was similar at baseline in patients with CTOs compared to those without CTOs. At 12-month follow-up, early invasive treatment resulted in higher PAQ summary scores in the non CTO arm (82.48 ± 22.79 vs. 67.83 ± 27.00, P&lt;0.001). In the CTO arm, while PAQ summary score was higher at 3 and 6 months in the early invasive arm, the difference was not significant at 12 months (76.18 ± 25.16 vs. 70.60 ± 24.24, P=0.14) Conclusions: Patients with CTO lesions present with higher Rutherford classification than their non-CTO counterparts and both have similar PAQ summary scores at presentation. Early invasive treatment for CTO and non-CTO lesions in PAD patients is associated with significant improvements in quality-of-life outcomes.

Diabetes, Hypertension, and Smoking Do Not Affect Outcomes of Iliofemoral Vein Stenting for Chronic Proximal Venous Outflow Obstruction

ObjectiveDiabetes, hypertension, and smoking are well-recognized risk factors for Peripheral Artery Disease (PAD), but little is known of their impact on chronic venous insufficiency (CVI). This study evaluates these factors in patients undergoing iliac vein stenting (IVS) for CVI. MethodsA registry of 708 patients who underwent IVS from August 2011 to June 2021 was retrospectively analyzed. Symptoms were quantified using venous clinical severity score (VCSS) and CEAP classification. Both major and minor reinterventions were recorded. Logistic regression models were used to determine the unadjusted and adjusted odds ratio (OR) of any reintervention. Log-rank test was used to assess differences in reintervention-free survival. ResultsThe prevalence of hypertension was 51.1% (N = 362), diabetes was 23.0% (N = 163), and smoking was 22.2% (N = 157). Patients with diabetes (3.6 vs 3.4; P = 0.062), hypertension (3.6 vs. 3.3; P < 0.001), and smoking (3.7 vs 3.4; P = 0.003) had higher CEAP scores than those without these comorbidities. Improvement in VCSS composite scores showed no differences postoperatively (Diabetes: P = 0.513; Hypertension: P = 0.053; Smoking: P = 0.608), at 1-year follow-up (Diabetes: P = 0.666; Hypertension: P = 0.681; Smoking: P = 0.745), or at 5-year follow-up (Diabetes: P = 0.525; Hypertension: P = 0.953; Smoking: P = 0.146). Diabetes (P = 0.454), smoking (P = 0.355), and hypertension (P = 0.727) were not associated with increased odds of major reintervention. Log-rank test similarly showed no differences in reintervention-free survival for major or minor reoperations between those with and without diabetes (P = 0.79), hypertension (P = 0.14), and smoking (P = 0.80). ConclusionsDiabetes, hypertension, and smoking were prevalent among CVI patients, but unlike in PAD patients, they had little to no impact on long-term outcomes or reinterventions after IVS.

Abstract 16530: Impact of Hyperuricemia on 5-year Clinical Outcomes in Patients With Critical Limb Ischemia Underwent Percutaneous Transluminal Angioplasty

Background: A growing evidence on the correlation between hyperuricemia and cardiovascular disease (CVD) has been previously reported. However, there have been limited data on the impact of hyperuricemia on long-term clinical outcomes in patients with critical limb ischemia (CLI) who underwent percutaneous transluminal angioplasty (PTA). Methods: A total, 425 peripheral artery disease (PAD) patients who underwent PTA for CLI were enrolled. The patients were divided into the hyperuricemia group (n=101) and the normal group (n=324). The primary endpoint was major adverse cerebral and cardiovascular event (MACCE), including death, myocardial infarction (MI), any coronary revascularization, and stroke, up to 5 years. The secondary endpoint was a major adverse limb event (MALE), including any repeated PTA, and target extremity surgery (TES). Inverse probability weighting (IPTW) analysis, derived from the logistic regression model, was performed to adjust for potential confounders. Results: After IPTW matching analysis, compared to the normal group, the hyperuricemia group was associated with a higher incidence of MACCE (20.7% vs. 13.6%, hazard ratio [HR], 1.65; 95% confidence interval [CI], 1.15 - 2.38, p=0.006) including non-cardiac death (11.7% vs. 6.3%, HR: 1.95, 95% CI: 1.19 - 3.19, p=0.006) and MALE (47.7% vs. 36.0%, HR: 1.62, 95% CI: 1.23-2.13, p=0.001) including non-target extremity revascularization (TER) (15.0% vs. 6.8%, HR: 2.42, 95% CI: 1.52-3.84, P&lt;0.001). Conclusions: In the present study, hyperuricemia was associated with worse clinical outcomes in patients with CLI following PTA during 5-year clinical follow-up. Efficacy of controlling hyperuricemia in improving clinical outcomes should be evaluated in the further studies.

Abstract 15167: The Use of Echocardiography in Patients With Advanced Peripheral Arterial Disease

Introduction: Patients with peripheral arterial disease (PAD) are at high risk of concomitant cardiac diseases. Transthoracic echocardiography (TTE) is a common imaging modality to assess cardiac function and is used as a screening tool, especially for patients with advanced PAD undergoing lower extremity revascularization (LER). The current study evaluates the incidental use of TTE in patients undergoing LER. Hypothesis: Patients with a perioperative TTE have improved outcomes compared to patients who do not undergo TTE. Methods: The electronic records of patients undergoing LER between 2013-2020 were reviewed. All TTE within 6 months of initial LER were captured. Patient characteristics and outcomes were compared between patients who underwent TTE and those who did not. Results: A total of 1,988 patients underwent LER, and 69.3% (N=1,377) had TTE. Patients in the TTE group were more likely to be African American and have diabetes mellitus, chronic kidney disease, and coronary artery disease. Patients with TTE were more likely to be on aspirin and undergo open/hybrid revascularization. There was no significant difference between the 2 groups in perioperative MI, major amputation, or mortality. Furthermore, patients with TTE had higher MALEs. (Table) However, there were no differences in MALE-free survival between the two groups (Figure 1) Conclusion: TTE was obtained in 69.3% of patients with advanced PAD undergoing LER but did not seem to be associated with outcomes in this institutional series. Further research is warranted to identify PAD patients that would benefit from TTE prior to LER.

Abstract 16424: Comparative Outcomes of Interventions for Peripheral Arterial Disease in Patients With Different Atherosclerotic Cardiovascular Disease Risk Estimates

Introduction: The atherosclerotic cardiovascular disease (ASCVD) Risk Estimator is an effective tool for predicting cardiovascular events. While peripheral arterial disease (PAD) represents an advanced form of atherosclerosis, ASCVD scores have not been studied in this patient population. This study will evaluate ASCVD risk scores in patients undergoing lower extremity revascularization (LER) for PAD and assess their impact on outcomes. Hypothesis: Patients with high ASCVD risk have worse outcomes after LER for PAD compared to those with lower risk. Methods: Electronic medical records of patients undergoing LER for PAD in a single center from 2013-2020 were reviewed. The ACC/AHA ASCVD estimator was used to calculate risk and categorize patients into risk groups before initial LER. Patient characteristics and outcomes were compared between those with high (≥20%) and lower (&lt;20%) risk scores. The lower risk group was composed of patients with intermediate, borderline, and low ASCVD risk. Results: A total of 635 patients were included and 429 (67.6%) had high ASCVD risk scores. Most patients in the lower risk group had intermediate (78%, N=161) risk, followed by low (12%, N=28), and borderline (8%, N=17) risk scores. High risk patients were more commonly males with more severe comorbidities. ( Table) Patients with high ASCVD risk had more long-term mortality (29% vs 19%, P=0.010) and inferior amputation-free survival ( Figure ) compared to those with lower risk. Conclusions: Most patients with PAD undergoing LER have high ASCVD risk. High ASCVD risk scores correlate with outcomes and may be useful for risk stratification in PAD patient populations with advanced atherosclerosis.

Inflammation Is a Histological Characteristic of Skeletal Muscle in Chronic Limb Threatening Ischemia

The loss of skeletal muscle is a prognostic factor in several diseases including in patients with chronic limb threatening ischemia (CLTI). Patients with CLTI also have a lower skeletal mass and area when compared to those with claudication. However, there are no currently available data regarding the histological characteristics of core muscles in patients with CLTI. This study aims to determine the differences in core skeletal muscles between patients with claudication and those with CLTI. The second aim is to evaluate the differences in myokines, which are molecules secreted by skeletal muscle, between patients with claudication and those with CLTI. An observational, prospective study was conducted from January 2018 to July 2022 involving consecutive patients with peripheral arterial disease (PAD). The clinical characteristics were registered. In PAD patients with surgical indication for common femoral artery approach, samples of sartorius skeletal muscle (and not from the limb muscles directly involved in the ischemic process) were collected. The samples were submitted to histological characterization on hematoxylin-eosin and to immunohistochemical analysis to detect CD45+ leukocytes and CD163+ macrophages. The extent of the inflammatory cells (leukocytes and macrophages) was semiquantitatively assessed using a 0-to-4 grade scale as follows: absent (0†), mild (†), moderate (††), severe (†††), and very severe (††††). Serum levels of myokines: irisin, myostatin, IL-8, and lL-6 were determined with multiplex bead-based immunoassay. 119 patients (mean age: 67.58±9.60years old, 79.80% males) 64 with claudication and 54 with CLTI were enrolled in the study. No differences were registered between patients with claudication and those with CLTI on age, gender, cardiovascular risk factors, and medication, except on smoking habits. There was a significantly higher prevalence of smokers and a higher smoking load in the claudication group. Samples of sartorius skeletal muscle from 40 patients (14 with claudication and 26 with CLTI) were submitted to histological analysis. No differences were found in skeletal muscle fibers preservation, trauma, or hemorrhage (on hematoxylin-eosin staining). However, in the immunohistochemistry study, we found more inflammatory cells CD45+ leukocytes in patients with CLTI when compared to those with claudication [CD45+≥moderate (††): claudication (n=14): 4; 28.57%; CLTI (n=25): 16; 64.00%; P=0.034]. Patients with CLTI also had higher tissue levels of CD163+ macrophages, but this difference was not significant [CD163+≥moderate (††): claudication (n=13): 7; 53.85%; CLTI (n=27): 21; 77.78%; P=0.122]. The serum levels of the myokines, irisin, and myostatin were below the lower limit of detection, in the majority of patients, so no valid results were obtained. However, patients with CLTI had a higher serum level of Interleukin (IL)-6 and IL-8. CLTI patients exhibit increased quantities of leukocytes in their sartorius muscle, as well as elevated serum levels of myokines IL-8 and IL-6. Inflamed skeletal muscle can contribute to the loss of muscle mass and account for the lower density of skeletal muscle observed in CLTI. Additionally, inflamed skeletal muscle may contribute to the development of systemic inflammation through the secretion of pro-inflammatory cytokines into the systemic circulation. Halting the inflammatory process could eventually improve the prognosis of CLTI patients.

DIAGNOSIS AND TREATMENT OF PERIPHERAL ARTERIAL DISEASE IN PATIENTS WITH DIABETES MELLITUS

Patients with endocrine disorders often present with concomitant cardiovascular diseases. Peripheral arterial disease (PAD) in individuals with type 2 diabetes exhibits various clinical characteristics and diverse consequences. One of its primary manifestations is macrovascular complications. Although atherosclerosis is the primary cause, other contributory factors come into play. Notably, individuals with diabetes experience a more severe clinical course, marked by higher amputation rates and significant differences in mortality. The ankle-brachial index (ABI) is the standard diagnostic tool for identifying arterial diseases, while angiography is considered the gold standard for assessing anatomical aspects. Effective management of comorbidities including type 2 diabetes, hypertension, and dyslipidemia, has a substantial impact on clinical progression. Atherosclerotic disease manifests through the narrowing of affected vessels, resulting in reduced blood flow. The diagnosis of PAD requires the management of risk factors, medication-based therapies, and interventions for lower extremity issues. Physical exercise is also a valuable approach for alleviating PAD symptoms and extending pain-free walking distances. For patients with refractory conditions, surgical interventions are recommended. In cases where atherosclerotic arterial lesions are minor, pose minimal surgical risk, and have a high likelihood of successful intervention, percutaneous transluminal angioplasty should be considered. Early intervention is recommended in the presence of rest pain, ischemic ulcers, or necrosis. Balloon angioplasty and stent placement have shown efficacy in symptom relief for many PAD patients. Recent technological advancements have expanded the use of endovascular procedures, even before considering traditional "open" methods. Lesion location and length are essential factors for the long-term success of percutaneous vascular interventions.

Automated Measurement of Vascular Calcification in Femoral Endarterectomy Patients Using Deep Learning.

Atherosclerosis, a chronic inflammatory disease affecting the large arteries, presents a global health risk. Accurate analysis of diagnostic images, like computed tomographic angiograms (CTAs), is essential for staging and monitoring the progression of atherosclerosis-related conditions, including peripheral arterial disease (PAD). However, manual analysis of CTA images is time-consuming and tedious. To address this limitation, we employed a deep learning model to segment the vascular system in CTA images of PAD patients undergoing femoral endarterectomy surgery and to measure vascular calcification from the left renal artery to the patella. Utilizing proprietary CTA images of 27 patients undergoing femoral endarterectomy surgery provided by Prisma Health Midlands, we developed a Deep Neural Network (DNN) model to first segment the arterial system, starting from the descending aorta to the patella, and second, to provide a metric of arterial calcification. Our designed DNN achieved 83.4% average Dice accuracy in segmenting arteries from aorta to patella, advancing the state-of-the-art by 0.8%. Furthermore, our work is the first to present a robust statistical analysis of automated calcification measurement in the lower extremities using deep learning, attaining a Mean Absolute Percentage Error (MAPE) of 9.5% and a correlation coefficient of 0.978 between automated and manual calcification scores. These findings underscore the potential of deep learning techniques as a rapid and accurate tool for medical professionals to assess calcification in the abdominal aorta and its branches above the patella.

Echo Intensity of Gastrocnemius Is Independently Associated with 6-Minute Walking Distance in Male Patients with Peripheral Arterial Disease.

Background and Objectives: This study aimed to examine the differences in the thickness and echo intensity (EI) of the gastrocnemius muscle measured via ultrasonography between healthy adults and patients with peripheral arterial disease (PAD) and to determine the associations of gastrocnemius thickness (GT) and EI within a 6 min walking distance (6MD) in patients with PAD. Materials and Methods: This cross-sectional study targeted 35 male patients with PAD (mean age, 73.7 years; mean body mass index [BMI], 23.5 kg/m2) and age- and gender-matched 73 male healthy adults (mean age, 73.2 years; mean BMI, 23.3 kg/m2). The gastrocnemius thickness (GT) and EI were measured using ultrasound. Both legs of patients with PAD were classified based on higher and lower ankle brachial pressure index (ABI), and the GTs and EIs with higher and lower ABI were compared with those of healthy adults. Multiple regression analysis incorporated 6MD as a dependent variable and each GT and EI with higher and lower ABI, age, and BMI as independent variables. Results: This study showed that GT was considerably greater in healthy adults than in both legs with higher and lower ABI (median values, 13.3 vs. 11.3 vs. 10.7, p < 0.01), whereas EI was lower in healthy adults than in the lower ABI leg (72.0 vs. 80.8 vs. 83.6, p < 0.05). The 6MD was shown to be substantially related to EI in both legs with higher and lower ABIs (p < 0.01) but not in the GT. Conclusions: In patients with PAD, the GT was lower, and EI was higher than in healthy adults. In addition, EIs in both legs with higher and lower ABIs were independently associated with 6MD in male PAD patients. This study showed that the EI measured via ultrasonography could become an important indicator for treatments for patients with PAD.