Therapy For Peripheral Arterial Disease Research Articles

Home-Based Walking Exercise and Supervised Treadmill Exercise in Patients With Peripheral Artery Disease

Few people with lower extremity peripheral artery disease (PAD) participate in supervised treadmill exercise covered by the Center for Medicare and Medicaid Services. In people with PAD, the benefits of home-based walking exercise, relative to supervised exercise, remain unclear. To study whether home-based walking exercise improves 6-minute walk (6MW) more than supervised treadmill exercise in people with PAD (defined as Ankle Brachial Index ≤0.90). Data were combined from 5 randomized clinical trials of exercise therapy for PAD using individual participant data meta-analyses, published from 2009 to 2022. Of the 5 clinical trials, 3 clinical trials compared supervised treadmill exercise to nonexercise control (N = 370) and 2 clinical trials compared an effective home-based walking exercise intervention to nonexercise control (N = 349). Individual participant-level data from 5 randomized clinical trials led by 1 investigative team were combined. The 5 randomized clinical trials included 3 clinical trials of supervised treadmill exercise and 2 effective home-based walking exercise interventions. Change in 6MW distance, maximum treadmill walking distance, and Walking Impairment Questionnaire at 6-month follow-up. The supervised treadmill exercise intervention consisted of treadmill exercise in the presence of an exercise physiologist, conducted 3 days weekly for up to 50 minutes per session. Home-based walking exercise consisted of a behavioral intervention in which a coach helped participants walk for exercise in or around home for up to 5 days per week for 50 minutes per session. A total of 719 participants with PAD (mean [SD] age, 68.8 [9.5] years; 46.5% female) were included (349 in a home-based exercise clinical trial and 370 in a supervised exercise trial). Compared with nonexercise control, supervised treadmill exercise was associated with significantly improved 6MW by 32.9 m (95% CI, 20.6-45.6; P < .001) and home-based walking exercise was associated with significantly improved 6MW by 50.7 m (95% CI, 34.8-66.7; P < .001). Compared with supervised treadmill exercise, home-based walking exercise was associated with significantly greater improvement in 6MW distance (between-group difference: 23.8 m [95% CI, 3.6, 44.0; P = .02]) but significantly less improvement in maximum treadmill walking distance (between-group difference:-132.5 m [95% CI, -192.9 to -72.1; P < .001]). In this individual participant data meta-analyses, compared with supervised exercise, home-based walking exercise was associated with greater improvement in 6MW in people with PAD. These findings support home-based walking exercise as a first-line therapy for walking limitations in PAD.

A viscoelastic constitutive model for human femoropopliteal arteries

High failure rates present challenges for surgical and interventional therapies for peripheral artery disease of the femoropopliteal artery (FPA). The FPA’s demanding biomechanical environment necessitates complex interactions with repair devices and materials. While a comprehensive understanding of the FPA’s mechanical characteristics could improve medical treatments, the viscoelastic properties of these muscular arteries remain poorly understood, and the constitutive model describing their time-dependent behavior is absent. We introduce a new viscoelastic constitutive model for the human FPA grounded in its microstructural composition. The model is capable of detailing the contributions of each intramural component to the overall viscoelastic response. Our model was developed utilizing fractional viscoelasticity and tested using biaxial experimental data with hysteresis and relaxation collected from 10 healthy human subjects aged 57 to 65 and further optimized for high throughput and automation. The model accurately described the experimental data, capturing significant nonlinearity and hysteresis that were particularly pronounced circumferentially, and tracked the contribution of passive smooth muscle cells to viscoelasticity that was twice that of the collagen fibers. The high-throughput parameter estimation procedure we developed included a specialized objective function and modifications to enhance convergence for the common exponential-type fiber laws, facilitating computational implementation. Our new model delineates the time-dependent behavior of human FPAs, which will improve the fidelity of computational simulations investigating device-artery interactions and contribute to their greater physical accuracy. Moreover, it serves as a useful tool to investigate the contribution of arterial constituents to overall tissue viscoelasticity, thereby expanding our knowledge of arterial mechanophysiology. Statement of significanceThe demanding biomechanical environment of the femoropopliteal artery (FPA) necessitates complex interactions with repair devices and materials, but the viscoelastic properties of these muscular arteries remain poorly understood with the constitutive model describing their time-dependent behavior being absent. We hereby introduce the first viscoelastic constitutive model for the human FPA grounded in its microstructures. This model was tested using biaxial mechanical data collected from 10 healthy human subjects between the ages of 57 to 65. It can detail the contributions of each intramural component to the overall viscoelastic response, showing that the contribution of passive smooth muscle cells to viscoelasticity is twice that of collagen fibers. The usefulness of this model as tool to better understand arterial mechanophysiology was demonstrated.

Impact of Hospital Volume on Long-Term Outcomes After Endovascular Therapy for Peripheral Artery Disease.

To investigate the association between annual hospital volume of endovascular therapy (EVT) and long-term outcomes in patients with lower-extremity peripheral artery disease (PAD). We identified patients who underwent percutaneous endovascular transluminal angioplasty and thrombectomy of the extremities or percutaneous endovascular removal in the Japanese Diagnosis Procedure Combination inpatient database from April 2014 to March 2020 linked to the Survey of Medical Institutions data. A generalized linear model analysis was performed to assess 12-month amputation, all-cause death, composite outcome (amputation and death), and readmission. We also analyzed length of hospital stay and total health care costs during the first hospitalization. Among 127 486 eligible patients, 31 579, 31 913, 31 999, and 31 995 were in the first (1-27 cases/year), second (28-44 cases), third (45-67 cases), and fourth (68-289 cases) quartiles, respectively. There were no significant differences in 12-month amputation among the second (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.90-1.04), third (OR, 1.00; 95% CI, 0.93-1.07), and fourth (OR, 1.00; 95% CI, 0.93-1.07) quartile volumes compared with the first quartile. Significant differences were observed in 12-month death (OR for fourth quartile with reference to the first quartile, 0.71; 95% CI, 0.65-0.76), composite outcome (OR, 0.84; 95% CI, 0.80-0.89), and readmission (OR, 1.05; 95% CI, 1.02-1.09). We found that the annual hospital volume of EVT was not associated with decreased 12-month amputation in patients with lower-extremity PAD. In contrast, all-cause death and composite outcome were significantly decreased in hospitals with the highest volume. The association between hospital volume of endovascular therapy and long-term adverse clinical outcomes remains unclear. The present analyses showed no significant differences in 12-month amputation rates among the hospital volumes, whereas higher-volume quartiles were significantly associated with decreased 12-month all-cause death rates and composite outcome. There was also a positive association in the length of stay between the first quartile volume and the others, while no significant difference in total health care costs among the quartiles was observed. Further investigations are needed, including insights into operator volume and procedural characteristics, to clarify the relationship between hospital volume and long-term adverse outcomes.

Abstract P130: Acute Angiotensin-(1-7) Infusion Does Not Improve Blood Pressure Or Leg Blood Flow In Participants With Peripheral Arterial Disease

Background: Peripheral arterial disease (PAD) is an atherosclerotic disease characterized by progressive narrowing of the arteries and pain in the lower extremities. Despite high clinical impact, our understanding of the causes and optimal therapies for PAD remains incomplete. Emerging evidence suggests that angiotensin (Ang)-(1-7), a protective renin-angiotensin system hormone, improves blood vessel function and reduces inflammation to protect against atherosclerosis in animal models; however, there are no data in clinical populations. Thus, in this study, we tested the hypothesis that Ang-(1-7) can decrease blood pressure and improve leg blood flow in PAD. Methods: PAD participants with intermittent claudication (n= 6, 2 females, 67±7 years) received intravenous infusion of Ang-(1-7) or saline on separate days in a randomized, double-blind, placebo-controlled, crossover study. Ang-(1-7) was infused in escalating doses at 1, 2, 4, 8, and 12 ng/kg/min, with each dose held for 10 minutes. Blood pressure (finometer), heart rate (electrocardiography), femoral blood flow (duplex Doppler), and muscle oxygen saturation (near-infrared spectroscopy) were measured continuously before and during the infusion. Data are shown as change from baseline (Δ mean±SEM). Results: Ang-(1-7) did not significantly alter systolic blood pressure (Ang: 7 ± 3 vs saline: 2 ± 2 mmHg, p = 0.16), diastolic blood pressure (Ang: 2 ± 2 vs saline: 3 ± 1 mmHg, p = 0.75), or heart rate (Ang: 0 ± 1 vs saline: 2 ± 2 beats/minute, p = 0.13). Ang-(1-7) also did not significantly increase femoral artery blood flow (Ang: 7.28 ± 14.23 vs saline: 14.35 ± 27.48 mL/minute, p = 0.85) or calf muscle oxygenation (0 ± 1 vs saline: 1 ± 1 %SpO 2 , p = 0.88) in the participants’ symptomatic leg. Conclusions: Acute infusion of Ang-(1-7) at low doses is not sufficient to lower blood pressure or improve measures of leg blood flow in participants with PAD. It is possible that higher or more sustained doses of Ang-(1-7) or intervening earlier in the disease process may be more effective, however, this has not been tested.

The ELEGANCE Registry: Working to Achieve Equity in Clinical Research Design

Summary Peripheral artery disease (PAD) disproportionately affects women and underrepresented, historically marginalized groups (UMGs); however, these patients are not well-represented in clinical research of PAD treatments. Most patients enrolled in trials are older white men. White women and underrepresented populations of any gender present differently and respond differently to therapies compared with white men. They must be represented in clinical studies of PAD in proportion to their numbers in the patient population to ensure generalizability of study findings and the development of optimal individualized care. The many obstacles to enrolling these populations in clinical studies include mistrust of the medical system, no proximity to clinics and providers who run clinical trials, limited understanding about the biomedical research process, language barriers, financial and transportation limitations, and inability to take time off from work or from caring for others in the household. Given the complexity of PAD and the need for clinical data from diverse patient populations that are not available from existing clinical trials, the authors created an international registry of patients treated with advanced therapies for PAD. The Drug-ELuting REGistry: ReAl-World Treatment of LesioNs in the Peripheral VasCulaturE (ELEGANCE) registry is a prospective international postmarket registry examining real-world use of drug-coated devices in patients with symptomatic PAD and includes several novel design elements aimed at enrolling at least 40% women and 40% underrepresented patients. As of December 1, 2022, over 800 patients were enrolled in the registry, ahead of target enrollment rates; of these, 44% are women and 47% are UMGs.

Keratose Hydrogel Drives Differentiation of Cardiac Vascular Smooth Muscle Progenitor Cells: Implications in Ischemic Treatment.

Peripheral artery disease (PAD) is a common vascular disorder in the extremity of limbs with limited clinical treatments. Stem cells hold great promise for thetreatment of PAD, but their therapeutic efficiency is limited due to multiple factors, such as poor engraftment and non-optimal selection of cell type. To date, stem cells from a variety of tissue sources have been tested, but little information is available regarding vascular smooth muscle cells (VSMCs) for PAD therapy. The present study examines the effects of keratose (KOS) hydrogels on c-kit+/CD31- cardiac vascular smooth muscle progenitor cell (cVSMPC) differentiation and the therapeutic potential of the resultant VSMCs in a mouse hindlimb ischemic model of PAD. The results demonstrated that KOS but not collagen hydrogel was able to drive the majority of cVSMPCs into functional VSMCs in a defined Knockout serum replacement (SR) medium in the absence of differentiation inducers. This effect could be inhibited by TGF-β1 antagonists. Further, KOS hydrogel increased expression of TGF-β1-associated proteins and modulated the level of free TGF-β1 during differentiation. Finally, transplantation of KOS-driven VSMCs significantly increased blood flow and vascular densities of ischemic hindlimbs. These findings indicate that TGF-β1 signaling is involved in KOS hydrogel-preferred VSMC differentiation and that enhanced blood flow are likely resulted from angiogenesis and/or arteriogenesis induced by transplanted VSMCs.

Treatment of Peripheral Artery Disease Using Injectable Biomaterials and Drug-Coated Balloons: Safety and Efficacy Perspective.

The possibility of injectable biomaterials being used in the therapy of peripheral artery disease (PAD) is investigated in this article. We conducted a thorough review of the literature on the use and efficacy of biomaterials (BMs) and drug-coated balloons (DCBs). These BMs included hydrogels, collagen scaffolds, and nanoparticles. These BMs could be used alone or in combination with growth factors, stem cells, or gene therapy. The treatment of peripheral artery disease with DCBs is increasingly common in the field of interventional angiology. Studies have been carried out to examine the effectiveness of paclitaxel-coated balloons such as PaccocathTM in lowering the frequency with which further revascularization operations are required. PCB angioplasty and angioplasty without paclitaxel did not significantly vary in terms of mortality, according to the findings of a recent meta-analysis that included the results of four randomized controlled studies. On the other hand, age was found to be a factor that predicted mortality. There was a correlation between the routine utilization of scoring balloon angioplasty along with DCBs and improved clinical outcomes in de novo lesions. In both preclinical and clinical testing, the SelutionTM DCB has demonstrated efficacy and safety, but further research is required to determine whether or not it is effective and safe over the long term. In addition, we reviewed the difficulties involved in bringing injectable BMs-based medicines to clinical trials, including the approval processes required by regulatory bodies. Injectable BMs have a significant amount of therapeutic promise for PAD, which highlights the need for more research and clinical studies to be conducted in this field. In conclusion, this research focuses on the potential of injectable BMs and DCBs in the treatment of PAD as well as the hurdles that must be overcome in order to translate these treatments into clinical trials. In this particular field, there is a demand for further research as well as clinical trials.

Abstract 550: Vascular And Muscle Recovery In Pre-clinical Model Of Peripheral Vascular Disease Using Intramuscular Estrogen Related Receptor Gamma Gene Therapy

Peripheral arterial disease (PAD) and critical limb ischemia (CLI) are caused by occlusion of blood vessels and characterized by muscle ischemia, weakness, and limb myopathy. Over 8-12 million Americans are affected by PAD, resulting in impaired mobility, increased cardiovascular risk, and limb amputation. Therapeutic strategies for simultaneously restoring blood flow, metabolism, and muscle recovery are currently lacking for PAD. We have previously shown in a transgenic mouse model that nuclear receptor Estrogen-related receptor gamma (ERRγ) is a central regulator of muscle metabolism and angiogenesis. Here, we investigated intramuscular (IM) gene therapy for PAD using AAV9-Esrrg in unilateral hindlimb ischemia (HLI) pre-clinical model. We first established in hindlimb muscles of C57Bl6/J mice that a single IM injection of 1X10^11 AAV9-Esrrg viral particles robustly increased ERRγ protein expression, resulting in induction of angiogenic and oxidative genes, higher capillary (CD31 immunostaining) density and SDH oxidative metabolic activity over AAV9-GFP injected control muscles. Subsequently, AAV9-Esrrg injection, 24 hours after HLI, increased ischemic neo-angiogenesis, markers of endothelial activation, and significantly improved blood flow recovery measured by laser Doppler flowmetry over AAV9-GFP injected controls. Moreover, ERRγ overexpression increased mitochondrial respiratory complex protein expression, which resulted in restored SDH oxidative metabolic capacity in ischemic muscle. More critically, AAV9-Esrrg restored myofibrillar size and mitigated ischemia-induced myopathy as revealed by myofiber size to number ratio quantification. In conclusion, we demonstrate that post-ischemic IM AAV9-Esrrg gene delivery rescues ischemic pathology by boosting metabolism and angiogenesis, underscoring Esrrg gene therapy or pharmacological activation as a highly promising strategy for treating PAD/CLI-related myopathy.

Gene Therapeutic Strategies for Peripheral Artery Disease and New Opportunities Provided by Adeno-Associated Virus Vectors.

Peripheral artery disease (PAD) is a vascular disorder caused by occlusive atherosclerosis, which commonly impairs blood flow to the lower extremities. The prevalence of PAD is increasing globally with >200 million people affected. PAD remains a growing global health problem as the population continues to age and diabetes incidence grows. Many patients with PAD, most notably those with critical limb ischemia, fail attempts at surgical and percutaneous intervention to improve blood flow and are at risk of amputation. Gene therapy provides an opportunity to change the clinical course of PAD in these patients via strategies that increase vascular supply through angiogenesis and arteriogenesis improving muscle perfusion and function in ischemic legs. This article discusses gene therapy approaches in the context of PAD, both intermittent claudication and critical limb ischemia, and the promise of adeno-associated virus-based strategies delivering not just VEGFs (vascular endothelial growth factors) but a range of other mediators as potential new therapeutics. We also highlight challenges and failures in the clinical translation of gene therapy for PAD and how at least some of these obstacles may be overcome using adeno-associated virus.

Microdialysis as a tool for antibiotic assessment in patients with diabetic foot: a review.

Diabetic foot is a serious late complication frequently caused by infection and ischaemia. Both require prompt and aggressive treatment to avoid lower limb amputation. The effectiveness of peripheral arterial disease therapy can be easily verified using triplex ultrasound, ankle-brachial/toe-brachial index examination, or transcutaneous oxygen pressure. However, the success of infection treatment is difficult to establish in patients with diabetic foot. Intravenous systemic antibiotics are recommended for the treatment of infectious complications in patients with moderate or serious stages of infection. Antibiotic therapy should be initiated promptly and aggressively to achieve sufficient serum and peripheral antibiotic concentrations. Antibiotic serum levels are easily evaluated by pharmacokinetic assessment. However, antibiotic concentrations in peripheral tissues, especially in diabetic foot, are not routinely detectable. This review describes microdialysis techniques that have shown promise in determining antibiotic levels in the surroundings of diabetic foot lesions.

Antithrombotic Therapy in Peripheral Artery Disease: Current Evidence and Future Directions.

Patients with peripheral artery disease (PAD) are at an increased risk of major adverse cardiovascular events, and those with disease in the lower extremities are at risk of major adverse limb events primarily driven by atherothrombosis. Traditionally, PAD refers to diseases of the arteries outside of the coronary circulation, including carotid, visceral and lower extremity peripheral artery disease, and the heterogeneity of PAD patients is represented by different atherothrombotic pathophysiology, clinical features and related antithrombotic strategies. The risk in this diverse population includes systemic risk of cardiovascular events as well as risk related to the diseased territory (e.g., artery to artery embolic stroke for patients with carotid disease, lower extremity artery to artery embolism and atherothrombosis in patients with lower extremity disease). Moreover, until the last decade, clinical data on antithrombotic management of PAD patients have been drawn from subanalyses of randomized clinical trials addressing patients affected by coronary artery disease. The high prevalence and related poor prognosis in PAD patients highlight the pivotal role of tailored antithrombotic therapy in patients affected by cerebrovascular, aortic and lower extremity peripheral artery disease. Thus, the proper assessment of thrombotic and hemorrhagic risk in patients with PAD represents a key clinical challenge that must be met to permit the optimal antithrombotic prescription for the various clinical settings in daily practice. The aim of this updated review is to analyze different features of atherothrombotic disease as well as current evidence of antithrombotic management in asymptomatic and secondary prevention in PAD patients according to each arterial bed.

Quality of life for patients with in-stent restenosis after interventional therapy of peripheral artery disease.

The aim of this study was to investigate the quality of life for patients with in-stent restenosis after interventional therapy of peripheral artery disease and the influencing factors. A total of 72 in-stent restenosis patients after interventional therapy of peripheral artery disease were enrolled, whose general data were obtained. SF-12 scale was used to evaluate the quality of life. Tilburg Frailty Scale was used to assess senile debilitation. Pittsburgh Quality Index Scale was used to evaluate sleep quality. Activity of Daily Living Scale was used to evaluate the self-care ability. The general data and in-stent restenosis-related indicators were compared between patients with low and high quality of life, respectively. Multivariate regression analysis was made on the factors affecting quality of life. The average total quality of life score of 72 patients was 74.06±19.26 points. The gender, Fontaine stage and smoking, Activity of Daily Living Scale score, painless walking distance, senile debilitation score, sleep quality score, white blood cells, and C-reactive protein had significant differences between the two groups, respectively (p<0.05). Multivariate regression analysis showed that the female gender, low Fontaine stage (OR=0.186), low senile debilitation score (OR=0.492), and high sleep quality score (OR=0.633) were the protective factors for high quality of life (all p<0.05), and the low Activity of Daily Living score (OR=1.282) was the risk factor for high quality of life (p<0.05). Quality of life of in-stent restenosis patients after interventional therapy of peripheral artery disease is low. Gender, Fontaine stage, senile debilitation, sleep quality, and Activity of Daily Living score are the influencing factors of quality of life for in-stent restenosis patients.

The Efficacy of HGF/VEGF Gene Therapy for Limb Ischemia in Mice with Impaired Glucose Tolerance: Shift from Angiogenesis to Axonal Growth and Oxidative Potential in Skeletal Muscle

Combined non-viral gene therapy (GT) of ischemia and cardiovascular disease is a promising tool for potential clinical translation. In previous studies our group has developed combined gene therapy by vascular endothelial growth factor 165 (VEGF165) + hepatocyte growth factor (HGF). Our recent works have demonstrated that a bicistronic pDNA that carries both human HGF and VEGF165 coding sequences has a potential for clinical application in peripheral artery disease (PAD). The present study aimed to test HGF/VEGF combined plasmid efficacy in ischemic skeletal muscle comorbid with predominant complications of PAD-impaired glucose tolerance and type 2 diabetes mellitus (T2DM). Male C57BL mice were housed on low-fat (LFD) or high-fat diet (HFD) for 10 weeks and metabolic parameters including FBG level, ITT, and GTT were evaluated. Hindlimb ischemia induction and plasmid administration were performed at 10 weeks with 3 weeks for post-surgical follow-up. Limb blood flow was assessed by laser Doppler scanning at 7, 14, and 21 days after ischemia induction. The necrotic area of m.tibialis anterior, macrophage infiltration, angio- and neuritogenesis were evaluated in tissue sections. The mitochondrial status of skeletal muscle (total mitochondria content, ETC proteins content) was assessed by Western blotting of muscle lysates. At 10 weeks, the HFD group demonstrated impaired glucose tolerance in comparison with the LFD group. HGF/VEGF plasmid injection aggravated glucose intolerance in HFD conditions. Blood flow recovery was not changed by HGF/VEGF plasmid injection either in LFD or HFD conditions. GT in LFD, but not in HFD conditions, enlarged the necrotic area and CD68+ cells infiltration. However, HGF/VEGF plasmid enhanced neuritogenesis and enlarged NF200+ area on muscle sections. In HFD conditions, HGF/VEGF plasmid injection significantly increased mitochondria content and ETC proteins content. The current study demonstrated a significant role of dietary conditions in pre-clinical testing of non-viral GT drugs. HGF/VEGF combined plasmid demonstrated a novel aspect of potential participation in ischemic skeletal muscle regeneration, through regulation of innervation and bioenergetics of muscle. The obtained results made HGF/VEGF combined plasmid a very promising tool for PAD therapy in impaired glucose tolerance conditions.

Changes in miRNA expression in patients with peripheral arterial vascular disease during moderate- and vigorous-intensity physical activity

BackgroundWalking is the preferred therapy for peripheral arterial disease in early stage. An effect of walking exercise is the increase of blood flow and fluid shear stress, leading, triggered by arteriogenesis, to the formation of collateral blood vessels. Circulating micro-RNA may act as an important information transmitter in this process. We investigated the acute effects of a single bout of 1) aerobic walking with moderate intensity; and 2) anaerobic walking with vigorous intensity on miRNA parameters related to vascular collateral formation.MethodsTen (10) patients with peripheral arterial disease with claudication (age 72 ± 7 years) participated in this two-armed, randomized-balanced cross-over study. The intervention arms were single bouts of supervised walking training at (1) vigorous intensity on a treadmill up to volitional exhaustion and (2) moderate intensity with individual selected speed for a duration of 20 min. One week of washout was maintained between the arms. During each intervention, heart rate was continuously monitored. Acute effects on circulating miRNAs and lactate concentration were determined using pre- and post-intervention measurement comparisons.ResultsVigorous-intensity walking resulted in a higher heart rate (125 ± 21 bpm) than the moderate-intensity intervention (88 ± 9 bpm) (p < 0.05). Lactate concentration was increased after vigorous-intensity walking (p = 0.005; 3.3 ± 1.2 mmol/l), but not after moderate exercising (p > 0.05; 1.7 ± 0.6 mmol/l). The circulating levels of miR-142-5p and miR-424-5p were up-regulated after moderate-intensity (p < 0.05), but not after vigorous-intensity training (p > 0.05).ConclusionModerate-intensity walking seems to be more feasible than vigorous exercises to induce changes of blood flow and endurance training-related miRNAs in patients with peripheral arterial disease. Our data thus indicates that effect mechanisms might follow an optimal rather than a maximal dose response relation. Steady state walking without the necessity to reach exhaustion seems to be better suited as stimulus.

Endothelial cell dysfunction: Implications for the pathogenesis of peripheral artery disease.

Peripheral artery disease (PAD) is caused by occluded or narrowed arteries that reduce blood flow to the lower limbs. The treatment focuses on lifestyle changes, management of modifiable risk factors and vascular surgery. In this review we focus on how Endothelial Cell (EC) dysfunction contributes to PAD pathophysiology and describe the largely untapped potential of correcting endothelial dysfunction. Moreover, we describe current treatments and clinical trials which improve EC dysfunction and offer insights into where future research efforts could be made. Endothelial dysfunction could represent a target for PAD therapy.

The fluctuation of skin perfusion pressure in hemodialysis patients treated with LDL apheresis therapy: A comparison of LDL adsorption and double filtration plasmapheresis.

There have been a number of reports suggesting that LDL apheresis, including LDL adsorption and double filtration plasmapheresis (DFPP), can be applied for the treatment of lower extremity peripheral arterial disease (PAD) in hemodialysis patients, whereas there is no definitive recommendation for the use of LDL apheresis. The change of skin perfusion pressure (SPP) during LDL apheresis was measured in every single treatment to determine the effect of LDL adsorption and DFPP on improving blood flow in lower extremity PAD hemodialysis patients. Eleven hemodialysis patients treated with more than two series of LDL apheresis were involved in the study. "One series" included 10 treatments of LDL apheresis according to the Japanese health care insurance system. In total, 320 treatments (32 series) of LDL apheresis were performed utilizing either LDL adsorption or DFPP treatment in 11 patients. The SPP values pre- and post-apheresis were recorded in 315 treatments (228 LDL adsorption and 87 DFPP). The SPP was significantly improved after both LDL adsorption (P < .001) and DFPP (P=.002) treatment. The median change of SPP was significantly larger in the LDL adsorption group (12.6 mm Hg, range: -48.5, 77.0 mm Hg) than in the DFPP group (6.7 mm Hg, range: -42.0, 72.5 mm Hg) (P=.003). The LDL adsorption consistently offered a significant increase in the SPP, whereas DFPP treatment seemed to have modest effects on the improvement of SPP compared to the LDL adsorption. These data indicate that LDL adsorption should be considered the primary LDL apheresis therapy for lower extremity PAD in hemodialysis patients to achieve improvement of blood flow.

Abstract 10271: Poor Response and Nonresponse to Clinically Available Supervised Exercise Therapy for Peripheral Artery Disease: A Pooled Analysis

Introduction: Nonresponse to supervised exercise therapy (SET) for symptomatic peripheral artery disease (PAD) is a known, but poorly understood, phenomenon affecting approximately one third of individuals. This study evaluated the prevalence and characteristics of poor response and nonresponse among patients with PAD participating in clinically-available SET programs. Methods: Data were pooled from four studies (conducted from 2015-2021) embedded within clinically-available SET programs in the Midwest. SET was 12 weeks in duration and included individualized treadmill walking or other exercise modalities (e.g., total body recumbent stepping, cycling) to moderate ischemia, according to patient ability. In addition to providing demographic and medical information, patients completed the 6-minute walk test (6MWT), Short Physical Performance Battery (SPPB), Walking Impairment Questionnaire (WIQ), and PAD Quality of Life Questionnaire (PADQOL) at baseline and 12 weeks. In post-hoc analyses, we examined the prevalence of nonresponse (including no change [≤0 m] or lack of a clinically meaningful change [≤9 m]) in the 6MWT total distance (primary outcome) and other objective and patient-reported outcomes. Results: A total of 130 patients (85%) completed SET. Mean (SD) age was 72.3 (8.4), BMI 30.2 (6.3), ABI 0.68 (0.23) and 53.1% of patients were male. Despite the overall improvement observed in 6MWT total distance (34.1 [57.1] meters), there was substantial inter-individual variability in changes in 6MWT total distance over 12 weeks, ranging from a 249.9-meter increase to a 104.6-meter decrease. The prevalence of nonresponse (no change/decline in performance) in 6MWT total distance was 24.6%. The prevalence of poor response (lack of a clinically meaningful improvement) was 32.3%. Similar patterns of poor and nonresponse were observed in both objective and patient-reported measures of physical function. Conclusions: The prevalence of nonresponse observed in these clinically available programs is similar to what has been reported in randomized controlled trials. Additional research should examine modifiable predictors of poor and nonresponse to inform programming and maximize an individual’s potential benefit from exercise therapy.

Abstract 11279: Reporting of Diversity and Inclusion in Clinical Trials of Exercise Therapy for Peripheral Vascular Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Introduction: Exercise therapy serves as a cornerstone of treatment for all patients with peripheral arterial disease (PAD); however, data suggest that women and minority groups with PAD suffer from disparate outcomes. Hypothesis: Randomized controlled trials (RCTs) of exercise therapy for PAD will demonstrate high rates of reporting and recruitment of women and minority groups. Methods: Databases were queried for RCTs that assessed the role of exercise therapy for PAD (Figure 1). Results: Only 2/47 (4%) of studies reported details of racial and ethnic subgroups (Figure 2). A meta-analysis of participation among non-white participants showed high heterogeneity (pooled effect 32%, I2 74%, p&lt;0.01, Figure 3) Meta-analysis of female recruitment and participation showed significant heterogeneity (pooled effect 26%, I2 76%, p&lt;0.01, Figure 4) with no improvement over time in meta-regression. Conclusions: Reporting and inclusion of women and minority groups remain low. Improved inclusion may help support the generalizability of the existing literature.

Peripheral artery disease with diabetes mellitus

Patients with peripheral artery disease and diabetes mellitus are vulnerable with an increased risk for morbidity, amputation and mortality compared to non-diabetic patients with peripheral artery disease. Despite huge efforts of the health care system diabetes mellitus still represents an important risk factor, also in people with peripheral artery disease. Regardless of the presence of diabetes mellitus people are often not aware of peripheral artery disease or do not achieve optimal therapy. Further, only few people with peripheral artery disease consult an angiologist or vascular surgeon. Aiming to reduce morbidity and mortality prevention, early detection and optimal therapy of peripheral artery disease and diabetes mellitus are crucial factors in adequate health-care management.

Antithrombotic therapy in peripheral arterial disease.

BackgroundPatients with peripheral arterial disease (PAD) are at increased risk for major adverse cardiovascular events (MACE) such as cardiovascular death, myocardial infarction, and stroke as well as major adverse limb events (MALE) such as amputation and acute limb ischemia. Therefore, prevention of thrombotic events is crucial to improve the prognosis of PAD patients. This review article concludes current evidence and guideline recommendations about antithrombotic therapy in PAD patients.Antithrombotic therapy is highly effective to reduce MACE and MALE events in PAD patients. Recently, the concept of dual pathway inhibition (low-dose rivaroxaban plus acetylic salicylic acid (ASA) has been tested in the COMPASS and VOYAGER-PAD trial. Compared to ASA alone dual pathway inhibition was superior to prevent MACE and MALE. After peripheral revascularization, in particular the risk for acute limb ischemia was reduced. In contrast, the risk for major bleeding is increased. Therefore, current guidelines recommend the combination of low-dose rivaroxaban and ASA in PAD patients with low bleeding risk. In patients with high bleeding risk, a single antiplatelet drug (preferable clopidogrel) is indicated. In patients with atherosclerotic vascular disease and indication for oral anticoagulation, no additional antiplatelet drug is necessary, as this would increase the risk of bleeding without improving the prognosis.ConclusionAntithrombotic treatment reduces MACE and MALE and is recommended in all patients with PAD. Individual bleeding risk should always be considered based on the current data situation and an individual benefit-risk assessment must be carried out.