Therapy For Peripheral Arterial Disease Research Articles

Benefits and Challenges of Drug-Coated Balloons in Peripheral Artery Disease: From Molecular Mechanisms to Clinical Practice.

Multiple clinical trials have reported favorable outcomes after drug-coated balloon therapy for peripheral artery disease in above-the-knee and below-the-knee lesions and in both de novo and in-stent restenosis. However, there are still insufficient data to identify and tackle the risk factors associated with a higher risk of restenosis, which is the primary concern for patients who are treated with an endovascular approach. A modern armamentarium, which includes improved lesion preparation techniques such as plaque modification balloons, mechanical atherectomy, intravascular lithotripsy, and imaging, is crucial for obtaining better long-term clinical outcomes. Moreover, a better understanding of the molecular properties of drug-coated balloons has led to improved devices that could tackle the shortcomings of previous generations. This comprehensive review focuses on drug-coated balloon technology as a tool to treat peripheral artery disease and the effects of the molecular mechanisms involved in preventing vascular restenosis.

MT39 Reporting Characteristics of Randomized Controlled Trials of Endovascular Therapy for Peripheral Artery Disease: A Systematic Review

MT39 Reporting Characteristics of Randomized Controlled Trials of Endovascular Therapy for Peripheral Artery Disease: A Systematic Review

Medical Therapy for Peripheral Artery Disease.

Patients with lower extremity peripheral artery disease (PAD) are at high risk for major adverse cardiovascular events (MACE) and major adverse limb events (MALE). This manuscript will review the current evidence for medical therapy in patients with PAD according to different clinical features and the overall cardiovascular (CV) risk. The management of PAD encompasses non-pharmacologic strategies, including lifestyle modification such as smoking cessation, supervised exercise, Mediterranean diet and weight loss as well as pharmacologic interventions, particularly for high risk patients. Benefits for reduction of CV and limb outcomes have been demonstrated for new therapies, including antithrombotic therapy (i.e., low-dose rivaroxaban plus aspirin), lipid lowering therapy (i.e., proprotein convertase subtilisin/kexin type 9inhibitors), and glucose lowering therapy (i.e., sodium-glucose cotransporter-2inhibitors and glucagon-like peptide-1receptor agonists). However, the adoption of these therapies in PAD remains suboptimal in practice. Implementation science studies have recently shown promising results in PAD patients. Comprehensive medical and non-medical management of PAD patients is crucial to improving patient outcomes, mitigating symptoms, and reducing the risk of MACE and MALE. A personalized approach, considering the patient's overall risk profile and preference, is essential for optimizing medical management of PAD.

AB077. SOH24AB_072. Is it reasonable to recommend best medical therapy for peripheral arterial disease based on general practitioner (GP) referral alone?—A correlation of vascular clinic outcomes to GP referrals for peripheral arterial disease

AB077. SOH24AB_072. Is it reasonable to recommend best medical therapy for peripheral arterial disease based on general practitioner (GP) referral alone?—A correlation of vascular clinic outcomes to GP referrals for peripheral arterial disease

Exercise Therapy for Peripheral Artery Disease.

To summarize evidence regarding exercise treatments for lower extremity peripheral artery disease (PAD). Supervised walking exercise is recommended by practice guidelines for PAD. Supervised treadmill exercise improves treadmill walking distance by approximately 180m and 6-min walk distance by 30-35m, compared to control. The Centers for Medicaid and Medicare Services covers 12weeks of supervised exercise, but most people with PAD do not participate. Home-based walking exercise may be more convenient and accessible than supervised exercise. In randomized clinical trials, home-based walking exercise interventions incorporating behavioral methods, such as accountability to a coach, goal-setting, and self-monitoring, improved 6-min walk distance by 40-54m, compared to control. Arm and leg ergometry also improved walking endurance for people with PAD, but efficacy compared to walking exercise remains unclear. Walking exercise is first-line therapy for PAD-related walking impairment and can be effective in either a supervised or a structured home-based setting.

Enabling Non-invasive Tracking of Vascular Endothelial Cells Derived from Induced Pluripotent Stem Cells Using Nuclear Imaging.

The absence of clinically applicable imaging techniques for continuous monitoring of transplanted cells poses a significant obstacle to the clinical translation of stem cell-based therapies for vascular regeneration. This study aims to optimize a clinically applicable, non-invasive imaging technique to longitudinally monitor vascular endothelial cells (ECs) for vascular regeneration in peripheral artery disease (PAD). Human induced pluripotent stem cells (HiPSCs) were employed to generate ECs (HiPSC-ECs). Lentiviral vectors encoding human sodium iodide symporter (hNIS) and enhanced green fluorescent protein (eGFP) genes were introduced to HiPSCs and HiPSC-ECs at varying multiplicities of infection (MOI). Through a combination of fluorescence microscopy and flow cytometry, an optimized transduction technique for introducing hNIS-eGFP into HiPSC-ECs was established. Subsequently, single-photon emission computed tomography (SPECT) was utilized for imaging of the transduced cells in vitro and in vivo after transplantation into the gastrocnemius muscle of nude mice. Lentiviral transduction resulted in sustained co-expression of hNIS and eGFP in HiPSC-ECs when transduced post-endothelial differentiation. An optimal MOI of five yielded over 90% hNIS-eGFP expression efficiency without compromising cell viability. hNIS-eGFP+ HiPSC-ECs exhibited 99mTc uptake and were detectable through SPECT in vitro. Additionally, intramuscular injection of hNIS-eGFP+ HiPSC-ECs with MatrigelTM into the hindlimbs of nude mice enabled real-time SPECT/CT tracking, from which a reduction in signal exceeding 80% was observed within 7days. This study establishes an optimized cell modification and imaging protocol for tracking transplanted cells. Future efforts will focus on enhancing cell survival and integration via improved delivery systems, thereby advancing the potential of cell-based therapies for PAD.

Gene therapy for peripheral arterial disease

Gene therapy for peripheral arterial disease

Medical Therapy for Peripheral Arterial Disease: A Small Step Before a Giant Leap

Medical Therapy for Peripheral Arterial Disease: A Small Step Before a Giant Leap

Open Surgical Therapy for Peripheral Artery Disease.

The surgical management of symptomatic peripheral artery disease (PAD) has changed in the last few decades. Improvement in endovascular technology has resulted in more complex lesion once reserved for open surgery being addressed in an endovascular fashion. Even with these advances, there are lesions and patients that are better managed with an open surgical procedure. The aim of this review is to describe the most commonly performed open surgical procedures for PAD. The recently published Best Endovascular versus Best Surgical Therapy (BEST-CLI) trial was an international, prospective, randomized controlled trial that aimed to investigate which revascularization (endovascular vs. surgical bypass) approach was superior for limb salvage. The evidence supports an open surgical bypass as an initial approach. The advancements made in the surgical management of PAD have provided options for patients who were once deemed poor surgical candidates. The goal continues to be utilization of the best available tools to address patient disease. In this current era, it is important to be familiar with the open surgical therapies.

Strategies to reduce out-of-pocket medication costs for Canadians with peripheral arterial disease.

Given that peripheral arterial disease (PAD) disproportionately affects people of lower socioeconomic status, out-of-pocket expenses for preventive medications are a major barrier to their use. We carried out a cost comparison of drug therapies for PAD to identify prescribing strategies that minimize out-of-pocket expenses for these medications. Between March and June 2019, we contacted outpatient pharmacies in Hamilton, Ontario, Canada, to assess pricing of pharmacologic therapies at dosages included in the 2016 American College of Cardiology/American Heart Association guideline for management of lower extremity PAD. We also gathered pricing information for supplementary charges, including delivery, pill splitting and blister packaging. We calculated prescription prices with and without dispensing fees for 30-day brand-name and generic prescriptions, and 90-day generic prescriptions. Twenty-four pharmacies, including hospital-based, independent and chain, were included in our sample. In the most extreme scenario, total 90-day medication costs could differ by up to $1377.26. Costs were affected by choice of agent within a drug class, generic versus brand-name drug, quantity dispensed, dispensing fee and delivery cost, if any. By opting for prescriptions for 90 days or as long as possible, selecting the lowest-cost generic drugs available in each drug class, and identifying dispensing locations with lower fees, prescribers can minimize out-of-pocket patient medication expenses. This may help improve adherence to guideline-recommended therapies for the secondary prevention of vascular events in patients with PAD.

Uptake and outcomes of supervised exercise therapy for peripheral artery disease: The importance of vascular medicine specialists at a large midwestern health care system during the first 5 years of CMS reimbursement.

Supervised exercise therapy (SET) is the cornerstone of medical therapy for symptomatic peripheral artery disease (PAD). Despite the efficacy of SET, initial reports following the 2017 Centers for Medicare and Medicaid Services (CMS) reimbursement decision indicate low SET uptake, referral, and completion. Vascular medicine specialists are key to the success of such programs. We examined rates of SET referral, completion, and outcomes in a health system with a robust SET program during the first 5 years of CMS reimbursement. A retrospective chart review of patients with PAD referred to SET between October 1, 2017 and December 31, 2022 was conducted. Patient demographic and medical characteristics, SET indication, referring provider specialty, SET participation (e.g., exercise modality, number of sessions, treadmill prescription), and outcomes were abstracted. Descriptive statistics, t-tests, and multiple linear regression were used to examine the sample, evaluate outcomes, and explore outcomes by relevant covariates (i.e., age, sex, referring provider specialty). Of 5320 patients with PAD, N = 773 were referred to SET; N = 415 enrolled and were included in the present study. Vascular medicine and vascular surgery specialists were the two primary sources of referrals (30.6% and 51.6%, respectively). A total of 207 patients (49.9%) completed SET. Statistically significant and clinically meaningful improvements were observed in all outcomes. SET referral and completion rates are low in the 5 years following CMS reimbursement, despite the advocacy of vascular medicine specialists. SET is effective in improving patient functional capacity and quality of life. Additional efforts are needed to increase both SET availability and referrals as part of comprehensive treatment of PAD.

Meta-Analysis of Duplex Surveillance Following Lower Limb Endovascular Intervention.

The aim of this systematic review was to identify the evidence in the literature for limb salvage with the introduction of duplex surveillance. A systematic review and meta-analysis was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines (PRISMA) methodology for all studies which compared a group undergoing clinical surveillance with a group undergoing combined clinical and duplex surveillance after endovascular therapy for peripheral arterial disease. MEDLINE, EMBASE, the Cochrane Database for Systematic Reviews, and ClinicalTrials.gov were searched for relevant studies by 2 reviewers. Studies were quality assessed using the ROBINS-I tool. An individual patient data survival analysis and meta-analysis for 1- and 2-year amputation outcomes using a random-effects model were performed. Two low-quality nonrandomized studies met the inclusion criteria. There was a statistically and clinically significant reduction in major amputation in patients undergoing combined clinical and duplex surveillance (log-rank p<0.001). The number needed to treat to prevent 1 amputation at 2 years was 5 patients. At 1 year, the odds ratio (OR) for amputation was 0.22, 95% confidence interval (CI)=0.10-0.48, with no statistical heterogeneity. At 2 years, the numbers of patients were low and the effect on amputation was less certain OR=0.25, 95% CI=0.04-1.58. Preliminary, low-quality data suggests that there may be a clinically significant reduction in major amputation with the introduction of duplex surveillance. It is recommended that a randomized controlled trial is performed to confirm these findings and identify the anatomical subgroups that benefit the most from surveillance. "Two low-quality studies reveal a significant clinical impact: combined clinical and duplex surveillance markedly reduces major amputations (log-rank p<0.001). At 1-year, the odds ratio for amputation is 0.22 (95% CI=0.10-0.48), emphasizing limb salvage benefits. Despite less certainty at 2-years, a notable absolute risk reduction of 19% is seen, with a number needed to treat of 5. This underscores the urgent need for a randomized controlled trial to validate findings and identify key subgroups. The meta-analysis strongly advocates implementing duplex surveillance for a year post-endovascular interventions, especially in patients fit for reintervention, with important considerations for cost-effectiveness and focused clinical trials."

Current Medical Therapy and Revascularization in Peripheral Artery Disease of the Lower Limbs: Impacts on Subclinical Chronic Inflammation.

Peripheral artery disease (PAD), coronary artery disease (CAD), and cerebrovascular disease (CeVD) are characterized by atherosclerosis and inflammation as their underlying mechanisms. This paper aims to conduct a literature review on pharmacotherapy for PAD, specifically focusing on how different drug classes target pro-inflammatory pathways. The goal is to enhance the choice of therapeutic plans by considering their impact on the chronic subclinical inflammation that is associated with PAD development and progression. We conducted a comprehensive review of currently published original articles, narratives, systematic reviews, and meta-analyses. The aim was to explore the relationship between PAD and inflammation and evaluate the influence of current pharmacological and nonpharmacological interventions on the underlying chronic subclinical inflammation. Our findings indicate that the existing treatments have added anti-inflammatory properties that can potentially delay or prevent PAD progression and improve outcomes, independent of their effects on traditional risk factors. Although inflammation-targeted therapy in PAD shows promising potential, its benefits have not been definitively proven yet. However, it is crucial not to overlook the pleiotropic properties of the currently available treatments, as they may provide valuable insights for therapeutic strategies. Further studies focusing on the anti-inflammatory and immunomodulatory effects of these treatments could enhance our understanding of the mechanisms contributing to the residual risk in PAD and pave the way for the development of novel therapies.

Dichotomous grouping of peripheral arterial calcification grades: A practical predictor of outcome after endovascular therapy in peripheral arterial disease.

There is a general agreement that arterial calcification affects the results of endovascular therapy for peripheral arterial disease (PAD). In addition to lacking evidence for their impact, existing calcification scores are complex, and not practical in everyday decision making. The global limb anatomic staging system (GLASS) adopted dichotomous grouping of calcification grades. In this study we aim to investigate the impact of peripheral arterial calcification scoring after dichotomous grouping on midterm outcomes following endovascular therapy for PAD. This prospective study included all consecutive patients with PAD indicated for endovascular therapy procedure who presented to our tertiary referral center in the period between October 2020 and October 2021. Patients were grouped into Group A (n = 40): with no-to mild calcification (PACSS grade 0,1 and 2), and Group B (n = 53): with severe calcification (PACSS grades 3 and 4). Primary endpoints included technical success rate, primary patency rates, and major adverse limb events rate (MALE) during 2years of follow-up. The mean age of the studied cases (n = 93) was 59.31 ± 6.46years (range 50-75). 70 patients (75.3%) were males, and 23 (24.7%) were females. There was no statistically significant difference between the two groups regarding technical success rate (97.5% in group A versus 94.33% in Group B, p = .457). The Primary patency rate after 1year was lower in group B (74%) compared to group A (89.7%), but this difference was not statistically significant (p = .059). However, the 2-year primary patency rate was significantly lower in group B compared to group A (64% versus 84.6% respectively, p = .034). MALE rate after 2years was significantly higher in group B (28%) as compared to group A (10.4%), P = .048. Studying suspected risk factors revealed that severe calcification was more common in patients with ischemic heart disease (34%) and chronic kidney disease (11%), P= .003 and .002 respectively. Logistic regression analysis showed that patients suffered from IHD and those with length of lesion ≥ 5cm are about five times more likely to have severe calcification compared to their counterparts (OR = 4.875, 95%CI = 1.293-18.383, p = .019, and OR = 4.513, 95% CI = 11.138-17.893, p = .032), respectively. The presence of severe calcification is associated with significantly lower midterm primary patency rates and higher rate of major adverse limb events after endovascular intervention for lower limb denovo arterial lesions.

Generation of Autologous Vascular Endothelial Cells for Patients with Peripheral Artery Disease.

Peripheral artery disease (PAD) is a prevalent cardiovascular disease with risks of limb loss. Our objective is to establish an autologous cell source for vascular regeneration to achieve limb salvage in PAD. Six PAD patients (age 50-80) were enrolled with their peripheral blood collected to derive vascular endothelial cells (ECs) with two different approaches: (1) endothelial progenitor cell (EPC) approach and (2) induced pluripotent stem cell (iPSC) approach. The iPSC approach successfully generated patient-specific ECs for all PAD patients, while the EPC approach did not yield any colony-forming ECs in any of the patients. The patient-derived iPSC-ECs expressed endothelial markers and exhibited endothelial functions. However, elevated inflammatory status with VCAM-1 expression was observed in the patient-derived cells. Pharmacological treatment with resveratrol resulted in patient-specific responses in cell viability and VCAM-1 expression. Our study demonstrates the potential of iPSC-ECs for autologous regenerative therapy in PAD, offering promise for personalized treatments for ischemic PAD.

Analysis of endovascular therapy for peripheral arterial disease in all German hospitals.

Background: The quality of vascular care has significantly improved in part by the expansion of endovascular techniques for the treatment of symptomatic peripheral artery disease (PAD) in recent years. In Germany these are primarily provided by the three disciplines of vascular surgery, angiology, and interventional radiology (IR). However, the relative contribute of angiologists to the total number of cases performed is unknown. Patients and methods: In the present study, we analysed the respective contribution of vascular surgery, angiology, and IR to the delivery of endovascular revascularisations in symptomatic PAD in Germany based on the legally mandatory quality reports representative for the reporting year 2018. Results: Vascular surgery is the most common speciality reporting procedures in German hospitals (n=579; 25.1%), followed by IR (n=264; 11.5%), angiology (n=189; 8.2%) and cardiology (n=17; 0.7%). The combination of vascular surgery and IR was reported in 202 (8.8%), vascular surgery and angiology in 167 (7.2%) and angiology and IR in 65 (2.8%) hospitals, and 63 (2.7%) hospitals reported the combination of all three disciplines. Not every department performed catheter interventions. The analysis of procedures per centre revealed that angiology centres provided the highest numbers for both basic procedures and more complex techniques such as atherectomy, rotational thrombectomy, lithoplasty, selective thrombolysis or the use of re-entry devices. In total, angiology centres provided 24.4% of the total procedures or 23.9% of the so-called basic procedures as a surrogate for patient numbers. Conclusions: While each of the disciplines contribute significantly to the endovascular procedures, angiology centres perform more procedures per centre and more complex procedures than the other disciplines highlighting the important quantitative and qualitative contribution of angiology specialists to the care of vascular patients. The inpatient catheter interventional care of patients with PAD is still too rarely carried out in a multi-disciplinary manner in Germany.

Conservative therapy and secondary prevention of PAD

Today, peripheral artery disease (PAD) is treated with the most modern endovascular and open surgical revascularisation procedures. But the short and long-term success of these interventions is decisively determined by the conservative therapy of PAD, which therefore represents the absolute basic therapy of every PAD. Conservative treatment addresses the "Big Five" of atherosclerosis risk factors: smoking, lack of exercise and overweight, diabetes, hypertension, and hyperlipidemia. Despite the knowledge that PAD as a peripheral manifestation of the systemic atherosclerosis needs the same risk factor management as e.g., coronary heart disease, not even every second PAD patient in Germany receives the required therapy. This paper presents the spectrum of both drug and non-drug strategies and focuses on aspects such as platelet inhibition and anticoagulation regimes, lipid-lowering options as well as the benefits and necessity of exercise programs to promote collaterals and improve quality of life by extending the pain-free walking distance. Proven strategies to overcome smoking addiction, use and purpose of vasoactive substances are highlighted as well as the potential risks of diabetic foot syndrome for limb salvage and prevention of wounds.

Endovascular therapy for peripheral arterial disease

In addition to conservative therapy with intensive walking training, endovascular revascularisation and open vascular surgical revascularisation are of high importance in the treatment of peripheral arterial disease. Over the past decades, endovascular therapy has developed considerably and is now the treatment of choice for most vascular segments. The use of different devices has been shown to be beneficial for different vessel segments. Primary stent angioplasty has been shown to be superior to balloon angioplasty with secondary stent implantation for the treatment of iliac lesions. Femoropopliteal, the use of paclitaxel-eluting balloon angioplasty is recommended. A mortality signal shown in a meta-analysis was not confirmed. With directional atherectomy and intravascular lithotripsy, different options for plaque modification are available. The cytostatic drug sirolimus as another antirestenotic substance still has to be investigated in large, randomised trials. A final assessment of the effectiveness and safety is not yet possible. Infrapopliteal balloon angioplasty remains the standard treatment. After interventional therapy, regular follow-up is recommended.

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.