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Background: Mitochondrial abnormalities exist in lower-extremity peripheral artery disease (PAD), yet the association of the ankle-brachial index (ABI) with mitochondrial respiration in gastrocnemius muscle is unknown. The association of gastrocnemius mitochondrial respiration with 6-minute walk distance in PAD is unknown. This objective of this study was to describe associations of the ABI with mitochondrial respiratory function in gastrocnemius muscle biopsies and associations of gastrocnemius mitochondrial respirometry with 6-minute walk distance in people with and without PAD., Methods: People with (ABI ⩽ 0.90) and without (ABI 1.00-1.40) PAD were enrolled. ABI and 6-minute walk distance were measured. Mitochondrial function of permeabilized myofibers from gastrocnemius biopsies was measured with high-resolution respirometry., Results: A total of 30 people with PAD (71.7 years, mean ABI: 0.64) and 68 without PAD (71.8 years, ABI: 1.17) participated. In non-PAD participants, higher ABI values were associated significantly with better mitochondrial respiration (Pearson correlation for maximal oxidative phosphorylation P CI+II : +0.29, p = 0.016). In PAD, the ABI correlated negatively and not significantly with mitochondrial respiration (Pearson correlation for P CI+II : -0.17, p = 0.38). In people without PAD, better mitochondrial respiration was associated with better 6-minute walk distance (Pearson correlation: +0.51, p < 0.001), but this association was not present in PAD (Pearson correlation: +0.10, p = 0.59)., Conclusions: Major differences exist between people with and without PAD in the association of gastrocnemius mitochondrial respiration with ABI and 6-minute walk distance. Among people without PAD, ABI and walking performance were positively associated with mitochondrial respiratory function. These associations were not observed in PAD., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. McDermott has received research support from Helixmith, Mars, and ArtAssist. The other authors have no conflicts of interest.

Introduction: Peripheral artery disease (PAD) is a well-described risk factor for mortality, but few studies have examined secular trends in mortality over time for patients with PAD. We characterized trends in mortality in patients with PAD in recent years among Medicare patients., Methods: We used Medicare claims to identify patients with a new diagnosis code for PAD between January 1, 2006 and December 31, 2018 using International Classification of Diseases (ICD) diagnosis codes. The primary outcome of interest was the 1-year all-cause age-adjusted mortality rate. Our secondary outcome was the 5-year all-cause mortality rate. Multivariable regression was used to identify factors which predict mortality at 1 year., Results: We identified 4,373,644 patients with a new diagnosis code for PAD during the study period. Between 2006 and 2018, 1-year all-cause age-adjusted mortality declined from 12.6% to 9.9% ( p < 0.001). One-year crude all-cause mortality also declined from 14.6% to 9.5% ( p < 0.001). Similar results were observed for 5-year age-adjusted mortality rates (40.9% to 35.2%, p < 0.001). Factors associated with increased risk of death at 1 year included age ⩾ 85 years (hazard ratio [HR] 3.030; 95% CI 3.008-3.053) and congestive heart failure (HR 1.86; 95% CI 1.85-1.88). Patients who were regularly dispensed statins, ace-inhibitors, beta-blockers, antithrombotic agents, and anticoagulants all had lower mortality (range OR 0.36; CI 0.35-0.37 for statins to OR 0.60; CI 0.59-0.61 for anticoagulants; all p < 0.001)., Conclusion: Among US Medicare patients diagnosed with PAD between 2006 and 2019, 1-year age-adjusted mortality declined by 2.7%. This decline in mortality among patients with PAD occurred in the context of a younger mean age of diagnosis of PAD and improved cardiovascular prevention therapy., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Marc P Bonaca reports grant support to Brigham and Women’s Hospital (BWH) from AstraZeneca, Amgen, Daiichi Sankyo, and Merck and grant support to Colorado Prevention Center Clinical Research from AstraZeneca, Amgen, and Sanofi. Mary M McDermott has received grant funding from Helixmith and research support from Helixmith, ChromaDex, Mars, Inc., ArtAssist, and Reserveage. The remaining authors have no conflicts of interest.

Objective: Home-based walking exercise is first-line therapy for peripheral artery disease (PAD), but benefits of home-based walking exercise are variable. This study evaluated whether specific clinical characteristics were associated with greater improvement after home-based walking exercise or with higher rates of serious adverse events (SAEs)., Methods: Data were combined from two randomized clinical trials comparing home-based walking exercise with control in PAD. The home-based exercise interventions used behavioral interventions to help participants adhere to exercise. The primary outcome was the proportion of PAD participants who improved 6-minute walk (6MW) by at least 20 meters. Serious adverse events consisted of overnight hospitalizations or death that occurred during the randomized clinical trial., Results: Of 376 participants with PAD (69.6 years; 54.5% Black; 49.5% women), 217 were randomized to exercise and 159 to control. Home-based exercise improved 6MW by at least 20 meters in 100 participants (54.9%), compared with 37 (28.0%) in control (odds ratio, 3.13; 95% confidence interval, 1.94-5.06; P < .001). Age, sex, race, comorbidities, baseline 6MW, and income did not significantly alter the effect of home-based exercise on improved 6MW. SAEs occurred in 28.1% and 23.3% of participants randomized to exercise and control, respectively (P = .29). There were statistically significant interactions, indicating that home-based exercise increased SAE rates, compared with control, in Black compared with non-Black participants (P interaction < .001), in those with vs without coronary artery disease (CAD) (P interaction < .001), and in people with vs without history of heart failure (P interaction = .005)., Conclusions: Among people with PAD, home-based exercise improved 6MW by at least 20 meters in 54.9% of people. Older age, female sex, Black race, and specific comorbidities were not associated with lower rates of attaining meaningful improvement in 6MW following home-based exercise. Further study is needed to establish whether certain patient characteristics, such as history of coronary artery disease, may affect SAE rates in patients with PAD participating in home-based exercise., Competing Interests: Disclosures M.M. reports grants from the National Heart, Lung, and Blood Institute and funding from the National Institute on Aging and the American Heart Association during the conduct of the study; research funding from Helixmith; and other research support from Mars and ArtAssist., (Copyright © 2024 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

People with lower extremity peripheral artery disease (PAD) have increased oxidative stress, impaired mitochondrial activity, and poor walking performance. NAD+ reduces oxidative stress and is an essential cofactor for mitochondrial respiration. Oral nicotinamide riboside (NR) increases bioavailability of NAD+ in humans. Among 90 people with PAD, this randomized double-blind clinical trial assessed whether 6-months of NR, with and without resveratrol, improves 6-min walk distance, compared to placebo, at 6-month follow-up. At 6-month follow-up, compared to placebo, NR significantly improved 6-min walk (+7.0 vs. -10.6 meters, between group difference: +17.6 (90% CI: + 1.8,+∞). Among participants who took at least 75% of study pills, compared to placebo, NR improved 6-min walk by 31.0 meters and NR + resveratrol improved 6-min walk by 26.9 meters. In this work, NR meaningfully improved 6-min walk, and resveratrol did not add benefit to NR alone in PAD. A larger clinical trial to confirm these findings is needed., (© 2024. The Author(s).)

Purpose of Review: To summarize evidence regarding exercise treatments for lower extremity peripheral artery disease (PAD)., Recent Findings: Supervised walking exercise is recommended by practice guidelines for PAD. Supervised treadmill exercise improves treadmill walking distance by approximately 180 m and 6-min walk distance by 30-35 m, compared to control. The Centers for Medicaid and Medicare Services covers 12 weeks 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 40-54 m, 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., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Competing Interests: Disclosures Dr McDermott has received research funding from Helixmith. She has received other research support from ArtAssist, Mars, ChromaDex, ReserveAge, and Helixmith. She has received funding from the National Institute on Aging, the National Heart Lung and Blood Institute, and the American Heart Association.

Objective: Among people with peripheral artery disease (PAD), perceived change in walking difficulty over time, compared with people without PAD, is unclear. Among people reporting no change in walking difficulty over time, differences in objectively measured change in walking performance between people with and without PAD are unknown., Methods: A total of 1289 participants were included. Eight hundred seventy-four participants with PAD (aged 71.1 ± 9.1 years) were identified from noninvasive vascular laboratories and 415 without PAD (aged 69.9 ± 7.6 years) were identified from people with normal vascular laboratory testing or general medical practices in Chicago. The Walking Impairment Questionnaire and 6-minute walk were completed at baseline and 1-year follow-up. The Walking Impairment Questionnaire assessed perceived difficulty walking due to symptoms in the calves or buttocks on a Likert scale (range, 0-4). Symptom change was determined by comparing difficulty reported at 1-year follow-up to difficulty reported at baseline., Results: At 1-year follow-up, 31.9% of participants with and 20.6% of participants without PAD reported walking difficulty that was improved (P < .01), whereas 41.2% vs 55%, respectively, reported walking difficulty that was unchanged (P < .01). Among all reporting no change in walking difficulty, participants with PAD declined in 6-minute walk, whereas participants without PAD improved (-10 vs +15 meters; mean difference, -25; 95% confidence interval, -38 to -13; P < .01)., Conclusions: Most people with PAD reported improvement or no change in walking difficulty from calf or buttock symptoms at one-year follow-up. Among all participants who perceived stable walking ability, those with PAD had significant greater declines in objectively measured walking performance, compared with people without PAD., Competing Interests: Disclosures M.M.M. reports other research support from ArtAssist, Helixmith, Mars, Chromadex, ReserveAge, and research funding from Regeneron and Helixmith., (Copyright © 2024. Published by Elsevier Inc.)

The pathophysiology of muscle damage in peripheral artery disease (PAD) includes increased oxidant production and impaired antioxidant defenses. Epicatechin (EPI), a naturally occurring flavanol, has antioxidant properties that may mediate the beneficial effects of natural products such as cocoa. In a phase II randomized trial, a cocoa-flavanol-rich beverage significantly improved walking performance compared with a placebo in people with PAD. In the present work, the molecular mechanisms underlying the therapeutic effect of cocoa flavanols were investigated by analyzing baseline and follow-up muscle biopsies from participants. Increases in nuclear factor erythroid 2-related factor 2 (Nrf2) target antioxidants heme oxygenase-1 (HO-1) and NAD(P)H dehydrogenase [quinone] 1 (NQO1) in the cocoa group were significantly associated with reduced accumulation of central nuclei, a myopathy indicator, in type II muscle fibers ( P = 0.017 and P = 0.023, respectively). Protein levels of the mitochondrial respiratory complex III subunit, cytochrome b-c1 complex subunit 2 (UQCRC2), were significantly higher in the cocoa group than in the placebo group ( P = 0.032), and increases in UQCRC2 were significantly associated with increased levels of Nrf2 target antioxidants HO-1 and NQO1 ( P = 0.001 and P = 0.035, respectively). Exposure of non-PAD human myotubes to ex vivo serum from patients with PAD reduced Nrf2 phosphorylation, an indicator of activation, increased hydrogen peroxide production and oxidative stress, and reduced mitochondrial respiration. Treatment of myotubes with EPI in the presence of serum from patients with PAD increased Nrf2 phosphorylation and protected against PAD serum-induced oxidative stress and mitochondrial dysfunction. Overall, these findings suggest that cocoa flavanols may enhance antioxidant capacity in PAD via Nrf2 activation. NEW & NOTEWORTHY The current study supports the hypothesis that in people with PAD, cocoa flavanols activate Nrf2, thereby increasing antioxidant protein levels, protecting against skeletal muscle damage, and increasing mitochondrial protein abundance. These results suggest that Nrf2 activation may be an important therapeutic target for improving walking performance in people with PAD.

Resistance training not only can improve or maintain muscle mass and strength, but also has favorable physiological and clinical effects on cardiovascular disease and risk factors. This scientific statement is an update of the previous (2007) American Heart Association scientific statement regarding resistance training and cardiovascular disease. Since 2007, accumulating evidence suggests resistance training is a safe and effective approach for improving cardiovascular health in adults with and without cardiovascular disease. This scientific statement summarizes the benefits of resistance training alone or in combination with aerobic training for improving traditional and nontraditional cardiovascular disease risk factors. We also address the utility of resistance training for promoting cardiovascular health in varied healthy and clinical populations. Because less than one-third of US adults report participating in the recommended 2 days per week of resistance training activities, this scientific statement provides practical strategies for the promotion and prescription of resistance training.

Disparities by sex, race, socioeconomic status, and geography exist in diagnosis, treatment, and outcomes for people with lower extremity peripheral artery disease (PAD). PAD prevalence is similar in men and women, but women have more atypical symptoms and undergo lower extremity revascularization at older ages compared to men. People who are Black have an approximately 2-fold higher prevalence of PAD, compared to people who are White and have more atypical symptoms, greater mobility loss, less optimal medical care, and higher amputation rates. Although fewer data are available for other races, people with PAD who are Hispanic have higher amputation rates than White people. Rates of amputation also vary by geography in the United States, with the highest rates of amputation in the southeastern United States. To improve PAD outcomes, intentional actions to eliminate disparities are necessary, including clinician education, patient education with culturally appropriate messaging, improved access to high-quality health care, science focused on disparity elimination, and health policy changes., Competing Interests: Funding Support and Author Disclosures Dr McDermott has received grant funding from Helixmith; and has received other research support from ArtAssist, Chromadex, ReserveAge, Mars, and Helixmith. Dr Hamburg has received honoraria from Novo Nordisk and Boston Scientific. Dr Pollak is a member of the Janssen Health Equity advisory group (unpaid). Dr Bonaca is the executive director of CPC, a nonprofit academic research organization affiliated with the University of Colorado, that receives or has received research grant and consulting funding between February 2021 and the present from Abbott Laboratories, Adamis Pharmaceuticals, Agios Pharmaceuticals, Alexion Pharma, Alnylam Pharmaceuticals, Amgen, Angionetics, ARCA Biopharma, Array BioPharma, AstraZeneca and Affiliates, Atentiv, Audentes Therapeutics, Bayer and Affiliates, Beth Israel Deaconess Medical Center, Better Therapeutics, Boston Clinical Research Institute, Bristol Myers Squibb, Cambrian Biopharma, Cardiol Therapeutics, CellResearch, Cook Medical, Covance, CSL Behring, Eidos Therapeutics, EP Trading, EPG Communication Holdings, Epizon Pharma, Esperion Therapeutics, Everly Well, Exicon Consulting, Faraday Pharmaceuticals, Foresee Pharmaceuticals, Fortress Biotech, HDL Therapeutics, HeartFlow, Hummingbird Bioscience, Insmed, Ionis Pharmaceuticals, IQVIA, JanOne Biotech Holdings, Janssen and Affiliates, Kaneka, Kowa Research Institute, Kyushu University, Lexicon Pharmaceuticals, LSG Kyushu University, Medimmune, Medpace, Merck & Affiliates, Novartis Pharmaceuticals, Novate Medical, Novo Nordisk, Pan Industry Group, Pfizer, PhaseBio Pharmaceuticals, PPD Development, Prairie Education and Research Cooperative, Prothena Biosciences, Regeneron Pharmaceuticals, Regio Biosciences, Rexgenero, Sanifit Therapeutics, Sanofi, Silence Therapeutics, Smith & Nephew, Stealth BioTherapeutics, the State of Colorado CCPD Grant, Brigham & Women’s Hospital, the Feinstein Institutes for Medical Research, the Thrombosis Research Institute, the University of Colorado, the University of Pittsburgh, VarmX, Virta Health, WCT Atlas, Worldwide Clinical Trials, WraSer, and Yale Cardiovascular Research Group; has received support from the American Heart Association Strategically Focused Research Network under awards 18SFRN3390085 (BWH-DH SFRN Center) and 18SFRN33960262 (BWH-DH Clinical Project); has modest stock holdings in Medtronic and Pfizer; and has received consulting fees from Audentes. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The process of peer review has been the gold standard for evaluating medical science, but significant pressures from the recent COVID-19 pandemic, new methods of communication, larger amounts of research, and an evolving publication landscape have placed significant pressures on this system. A task force convened by the American College of Cardiology identified the 5 most significant controversies associated with the current peer-review process: the effect of preprints, reviewer blinding, reviewer selection, reviewer incentivization, and publication of peer reviewer comments. Although specific solutions to these issues will vary, regardless of how scientific communication evolves, peer review must remain an essential process for ensuring scientific integrity, timely dissemination of information, and better patient care. In medicine, the peer-review process is crucial because harm can occur if poor-quality data or incorrect conclusions are published. With the dramatic increase in scientific publications and new methods of communication, high-quality peer review is more important now than ever., Competing Interests: Funding Support and Author Disclosures Dr Kusumoto is chair of the Peer Review Task Force; and is chair of the ACC Scientific Publications Committee. Dr Bittl is a member of the ACC Scientific Publications Committee. Dr Creager is a member of the ACC Scientific Publications Committee. Dr Dauerman is associate editor of the Journal of the American College of Cardiology; has received research funding from Medtronic and Boston Scientific; and is a consultant for Medtronic and Boston Scientific. Dr Lala is deputy editor of the Journal of Cardiac Failure; and has received speaker honoraria from Zoll Medical and Abbott. Dr McDermott is deputy editor of JAMA; has received research funding from Regeneron and Helixmith; and has received other research support from Helixmith, ArtAssist, Hershey, Mars, Chromadex, and ResearveAge. Ms Varieur Turco is divisional senior director of publishing for the ACC. Dr Taqueti is immediate past chair of the ACC Scientific Publications Committee; and is chair of the ACC Digital Transformation Committee. Dr Fuster is editor-in-chief of the Journal of the American College of Cardiology., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background Overweight and obesity are associated with adverse functional outcomes in people with peripheral artery disease (PAD). The effects of weight loss in people with overweight/obesity and PAD are unknown. Methods The PROVE (Promote Weight Loss in Obese PAD Patients to Prevent Mobility Loss) Trial is a multicentered randomized clinical trial with the primary aim of testing whether a behavioral intervention designed to help participants with PAD lose weight and walk for exercise improves 6-minute walk distance at 12-month follow-up, compared with walking exercise alone. A total of 212 participants with PAD and body mass index ≥25 kg/m 2 will be randomized. Interventions are delivered using a Group Mediated Cognitive Behavioral intervention model, a smartphone application, and individual telephone coaching. The primary outcome is 12-month change in 6-minute walk distance. Secondary outcomes include total minutes of walking exercise/wk at 12-month follow-up and 12-month change in accelerometer-measured physical activity, the Walking Impairment Questionnaire distance score, and the Patient-Reported Outcomes Measurement Information System mobility questionnaire. Tertiary outcomes include 12-month changes in perceived exertional effort at the end of the 6-minute walk, diet quality, and the Short Physical Performance Battery. Exploratory outcomes include changes in gastrocnemius muscle biopsy measures of mitochondrial cytochrome C oxidase activity, mitochondrial biogenesis, capillary density, and inflammatory markers. Conclusions The PROVE randomized clinical trial will evaluate the effects of exercise with an intervention of coaching and a smartphone application designed to achieve weight loss, compared with exercise alone, on walking performance in people with PAD and overweight/obesity. Results will inform optimal treatment for the growing number of patients with PAD who have overweight/obesity. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04228978.

Importance: 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., Objective: 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 Sources: Data were combined from 5 randomized clinical trials of exercise therapy for PAD using individual participant data meta-analyses, published from 2009 to 2022., Study Selection: 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)., Data Extraction and Synthesis: 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., Main Outcomes and Measures: 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., Results: 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])., Conclusions and Relevance: 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.

Background: Peripheral artery disease (PAD) is underdiagnosed due to poor patient and clinician awareness. Despite this, no widely accepted PAD screening is recommended., Objectives: The authors used machine learning to develop an automated risk stratification tool for identifying patients with a high likelihood of PAD., Methods: Using data from the electronic health record (EHR), ankle-brachial indices (ABIs) were extracted for 3,298 patients. In addition to ABI, we extracted 60 other patient characteristics and used a random forest model to rank the features by association with ABI. The model identified several features independently correlated with PAD. We then built a logistic regression model to predict PAD status on a validation set of patients (n = 1,089), an external cohort of patients (n = 2,922), and a national database (n = 2,488). The model was compared to an age-based and random forest model., Results: The model had an area under the curve (AUC) of 0.68 in the validation set. When evaluated on an external population using EHR data, it performed similarly with an AUC of 0.68. When evaluated on a national database, it had an AUC of 0.72. The model outperformed an age-based model (AUC: 0.62; P < 0.001). A random forest model with inclusion of all 60 features did not perform significantly better (AUC: 0.71; P = 0.31)., Conclusions: Statistical techniques can be used to build models which identify individuals at high risk for PAD using information accessible from the EHR. Models such as this may allow large health care systems to efficiently identify patients that would benefit from aggressive preventive strategies or targeted-ABI screening.

Background: The distal superficial femoral artery (SFA) is most commonly affected in peripheral artery disease (PAD). The effects of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab added to statin therapy on SFA atherosclerosis, downstream flow, and walking performance are unknown., Methods: Thirty-five patients with PAD on maximally tolerated statin therapy were recruited. Patients were randomized to alirocumab 150 mg subcutaneously ( n = 18) or matching placebo ( n = 17) therapy every 2 weeks for 1 year. The primary outcome was change in SFA plaque volume by black blood magnetic resonance imaging (MRI). Secondary outcomes were changes in calf muscle perfusion by cuff/occlusion hyperemia arterial spin labeling MRI, 6-minute walk distance (6MWD), low-density lipoprotein (LDL) cholesterol, and other biomarkers., Results: Age (mean ± SD) was 64 ± 8 years, 20 (57%) patients were women, 17 (49%) were Black individuals, LDL was 107 ± 36 mg/dL, and the ankle-brachial index 0.71 ± 0.20. The LDL fell more with alirocumab than placebo (mean [95% CI]) (-49.8 [-66.1 to -33.6] vs -7.7 [-19.7 to 4.3] mg/dL; p < 0.0001). Changes in SFA plaque volume and calf perfusion showed no difference between groups when adjusted for baseline (+0.25 [-0.29 to 0.79] vs -0.04 [-0.47 to 0.38] cm 3 ; p = 0.37 and 0.22 [-8.67 to 9.11] vs 3.81 [-1.45 to 9.08] mL/min/100 g; p = 0.46, respectively), nor did 6MWD., Conclusion: In this exploratory study, the addition of alirocumab therapy to statins did not alter SFA plaque volume, calf perfusion or 6MWD despite significant LDL lowering. Larger studies with longer follow up that include plaque characterization may improve understanding of the effects of intensive LDL-lowering therapy in PAD (ClinicalTrials.gov Identifier: NCT02959047) .

Background: Few effective therapies exist to improve lower extremity muscle pathology and mobility loss due to peripheral artery disease (PAD), in part because mechanisms associated with functional impairment remain unclear., Methods: To better understand mechanisms of muscle impairment in PAD, we performed in-depth transcriptomic and proteomic analyses on gastrocnemius muscle biopsies from 31 PAD participants (mean age, 69.9 years) and 29 age- and sex-matched non-PAD controls (mean age, 70.0 years) free of diabetes or limb-threatening ischemia., Results: Transcriptomic and proteomic analyses suggested activation of hypoxia-compensatory mechanisms in PAD muscle, including inflammation, fibrosis, apoptosis, angiogenesis, unfolded protein response, and nerve and muscle repair. Stoichiometric proportions of mitochondrial respiratory proteins were aberrant in PAD compared to non-PAD, suggesting that respiratory proteins not in complete functional units are not removed by mitophagy, likely contributing to abnormal mitochondrial activity. Supporting this hypothesis, greater mitochondrial respiratory protein abundance was significantly associated with greater complex II and complex IV respiratory activity in non-PAD but not in PAD. Rate-limiting glycolytic enzymes, such as hexokinase and pyruvate kinase, were less abundant in muscle of people with PAD compared with non-PAD participants, suggesting diminished glucose metabolism., Conclusions: In PAD muscle, hypoxia induces accumulation of mitochondria respiratory proteins, reduced activity of rate-limiting glycolytic enzymes, and an enhanced integrated stress response that modulates protein translation. These mechanisms may serve as targets for disease modification., Competing Interests: Disclosures None.

Background Mitochondrial abnormalities exist in gastrocnemius muscle of people with peripheral artery disease (PAD). Whether abnormalities in mitochondrial biogenesis and autophagy are associated with greater ischemia or walking impairment in PAD is unknown. Methods and Results Protein markers of mitochondrial biogenesis and autophagy and the abundance of mitochondrial electron transport chain complexes were quantified in gastrocnemius muscle biopsies from people with and without PAD. Their 6-minute walk distance and 4-m gait speed were measured. Sixty-seven participants (mean age 65.0 years [±6.8], 16 [23.9%] women, 48 [71.6%] Black) were enrolled, including 15 with moderate to severe PAD (ankle brachial index [ABI] <0.60), 29 with mild PAD (ABI 0.60-0.90), and 23 without PAD (ABI 1.00-1.40). Abundance of all electron transport chain complexes was significantly higher in participants with lower ABI (eg, complex I: 0.66, 0.45, 0.48 arbitrary units [AU], respectively, P trend=0.043). Lower ABI values were associated with a higher LC3A/B II-to-LC3A/B I (microtubule-associated protein 1A/1B-light chain 3) ratio (2.54, 2.31, 2.15 AU, respectively, P trend=0.017) and reduced abundance of the autophagy receptor p62 (0.71, 0.69, 0.80 AU, respectively, P trend=0.033). The abundance of each electron transport chain complex was positively and significantly associated with 6-minute walk distance and 4-m gait speed at usual and fast pace only among participants without PAD (eg, complex I: r =0.541, P =0.008; r =0.477, P =0.021; r =0.628, P =0.001, respectively). Conclusions These results suggest that accumulation of electron transport chain complexes in gastrocnemius muscle of people with PAD may be because of impaired mitophagy in the setting of ischemia. Findings are descriptive, and further study in larger sample sizes is needed.

Background: This study evaluated the association of smoking with mitochondrial function in gastrocnemius muscle of people with peripheral artery disease (PAD)., Methods: Participants were enrolled from Chicago, Illinois and consented to gastrocnemius biopsy. Mitochondrial oxidative capacity was measured in muscle with respirometry. Abundance of voltage-dependent anion channel (VDAC) (mitochondrial membrane abundance), peroxisome proliferator-activated receptor-γ coactivator (PGC-1α) (mitochondrial biogenesis), and electron transport chain complexes I-V were measured with Western blot., Results: Fourteen of 31 people with PAD (age 72.1 years, ABI 0.64) smoked cigarettes currently. Overall, there were no significant differences in mitochondrial oxidative capacity between PAD participants who currently smoked and those not currently smoking (complex I+II-mediated oxidative phosphorylation: 86.6 vs 78.3 pmolO 2 /s/mg, respectively [ p = 0.39]). Among participants with PAD, those who currently smoked had a higher abundance of PGC-1α ( p < 0.01), VDAC ( p = 0.022), complex I ( p = 0.021), and complex III ( p = 0.021) proteins compared to those not currently smoking. People with PAD who currently smoked had lower oxidative capacity per VDAC unit (complex I+II-mediated oxidative phosphorylation [137.4 vs 231.8 arbitrary units, p = 0.030]) compared to people with PAD not currently smoking. Among people without PAD, there were no significant differences in any mitochondrial measures between currently smoking ( n = 5) and those not currently smoking ( n = 63)., Conclusions: Among people with PAD, cigarette smoking may stimulate mitochondrial biogenesis to compensate for reduced oxidative capacity per unit of mitochondrial membrane, resulting in no difference in overall mitochondrial oxidative capacity according to current smoking status among people with PAD. However, these results were cross-sectional and a longitudinal study is needed.

Objective: This study identified barriers to participation in supervised exercise therapy covered by the Centers for Medicare and Medicaid Services (CMS), reported by people with lower extremity peripheral artery disease (PAD)., Methods: People with PAD participating in research studies of walking impairment due to PAD in the Chicagoland area were asked to complete a questionnaire between March 15, 2019, and July 12, 2022, assessing their experience and attitudes about supervised exercise therapy. Participants were identified using mailed postcards to people aged 50 and older in Chicagoland, from medical centers in Chicago, and using bus and train advertisements. The questionnaire was developed based on focus group feedback from people with PAD., Results: Of 516 participants with PAD approached, 489 (94.8%) completed the questionnaire (mean age: 71.0 years [standard deviation: 8.7], mean ankle-brachial index: 0.71 [standard deviation: 0.25]; 204 [41.7%] women and 261 [53.4%] Black). Of the 489 participants, 416 (85.1%) reported that their physician had never prescribed or recommended supervised exercise therapy. Overall, 357 (73.2%) reported willingness to travel three times weekly to the medical center for supervised exercise participation. However, of these, 214 (59.9%) reported that they were unwilling or unable to pay the $11 per exercise session copay required for supervised exercise covered by CMS. Of 51 people with PAD who reported prior participation in supervised exercise, only 5 (9.8%) completed the 12 weeks of supervised exercise therapy covered by CMS and 29 (56.9%) completed 6 or fewer weeks. Of 131 (26.8%) unwilling to travel three times weekly to a center for supervised exercise, the most common reasons for unwillingness to participate were "too time-consuming" (55.0%), "too inconvenient" (45.8%), and "lack of interest in treadmill exercise" (28.2%)., Conclusions: Approximately 2 to 4 years after CMS began covering supervised exercise for PAD, most people with PAD in this study from a large urban area had not participated in supervised exercise therapy. Of those who participated, most completed fewer than half of the sessions covered by CMS. The required CMS copayment was a common barrier to supervised exercise participation by people with PAD., (Copyright © 2022 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background Supervised exercise therapy (SET) is the first-line therapy for walking impairment in peripheral artery disease (PAD). This study evaluated the association between attendance at SET and improved walking performance, compared with a control group, in PAD. Methods and Results Data from 2 randomized clinical trials of SET for PAD were combined. In each trial, participants were randomized to 3 times weekly supervised treadmill exercise or an attention control group for 6 months (maximum, 77 exercise sessions). Participants randomized to SET were categorized into tertiles, according to the proportion of exercise sessions they attended. Results adjusted for age, sex, race, baseline walking performance, comorbidities, and other potential confounders. A total of 272 participants with PAD (mean age, 67.9±9.3 years; 44% women; 61% Black race) were included. For participants randomized to SET, tertiles of attendance rates at exercise sessions were as follows: 11% to 68% (N=45), 69% to <85% (N=46), and ≥85% (N=46). Compared with control, mean improvement in 6-minute walk was significantly greater in each SET tertile: mean (95% CI) for tertile 1, 27.9 m (1.3-54.4 m; P =0.04), tertile 2, 38.2 m (12.2-64.2 m; P =0.001), and tertile 3, 56.9 m (29.9-83.8 m; P <0.0001). Among participants randomized to SET, greater SET attendance was associated with greater improvement in 6-minute walk distance (overall P for trend=0.025). Compared with control, improvement in maximal treadmill walking time was greater in each SET attendance tertile: tertile 1 (3.3 minutes [95% CI, 1.7-4.8 minutes]; P <0.0001), tertile 2 (3.8 minutes [95% CI, 2.3-5.3 minutes]; P <0.0001), and tertile 3 (5.4 minutes [95% CI, 3.9-7.0 minutes]; P :<0.0001). Among participants randomized to SET, greater attendance at SET was not significantly associated with greater improvement in maximal treadmill walking time (overall P for trend=0.064). Conclusions Among people with PAD randomized to SET, better attendance at exercise sessions was associated with significantly greater 6-minute walk improvement. Among all participants with PAD, even relatively low SET attendance was associated with significantly greater improvement in walking performance, compared with a control group who did not exercise. Registration URL: https://clinicaltrials.gov/ct2/show/NCT01408901. URL: https://clinicaltrials.gov/ct2/show/NCT00106327.

Background Peripheral artery disease (PAD) is associated with gastrocnemius muscle abnormalities. However, the biological pathways associated with gastrocnemius muscle dysfunction and their associations with progression of PAD are largely unknown. This study characterized differential gene and microRNA (miRNA) expression in gastrocnemius biopsies from people without PAD compared with those with PAD. Participants with PAD included those with and without PAD progression. Methods and Results mRNA and miRNA sequencing were performed to identify differentially expressed genes, differentially expressed miRNAs, mRNA-miRNA interactions, and associated biological pathways for 3 sets of comparisons: (1) PAD progression (n=7) versus non-PAD (n=7); (2) PAD no progression (n=6) versus non-PAD; and (3) PAD progression versus PAD no progression. Immunohistochemistry was performed to determine gastrocnemius muscle fiber types and muscle fiber size. Differentially expressed genes and differentially expressed miRNAs were more abundant in the comparison of PAD progression versus non-PAD compared with PAD with versus without progression. Among the top significant cellular pathways in subjects with PAD progression were muscle contraction or development, transforming growth factor-beta, growth/differentiation factor, and activin signaling, inflammation, cellular senescence, and notch signaling. Subjects with PAD progression had increased frequency of smaller Type 2a gastrocnemius muscle fibers in exploratory analyses. Conclusions Humans with PAD progression exhibited greater differences in the number of gene and miRNA expression, biological pathways, and Type 2a muscle fiber size compared with those without PAD. Fewer differences were observed between people with PAD without progression and control patients without PAD. Further study is needed to confirm whether the identified transcripts may serve as potential biomarkers for diagnosis and progression of PAD.

Importance: Patients with lower extremity peripheral artery disease (PAD) have reduced lower extremity perfusion, impaired lower extremity skeletal muscle function, and poor walking performance. Telmisartan (an angiotensin receptor blocker) has properties that reverse these abnormalities., Objective: To determine whether telmisartan improves 6-minute walk distance, compared with placebo, in patients with lower extremity PAD at 6-month follow-up., Design, Setting, and Participants: Double-blind, randomized clinical trial conducted at 2 US sites and involving 114 participants. Enrollment occurred between December 28, 2015, and November 9, 2021. Final follow-up occurred on May 6, 2022., Interventions: The trial randomized patients using a 2 × 2 factorial design to compare the effects of telmisartan plus supervised exercise vs telmisartan alone and supervised exercise alone and to compare telmisartan alone vs placebo. Participants with PAD were randomized to 1 of 4 groups: telmisartan plus exercise (n = 30), telmisartan plus attention control (n = 29), placebo plus exercise (n = 28), or placebo plus attention control (n = 27) for 6 months. The originally planned sample size was 240 participants. Due to slower than anticipated enrollment, the primary comparison was changed to the 2 combined telmisartan groups vs the 2 combined placebo groups and the target sample size was changed to 112 participants., Main Outcomes and Measures: The primary outcome was the 6-month change in 6-minute walk distance (minimum clinically important difference, 8-20 m). The secondary outcomes were maximal treadmill walking distance; Walking Impairment Questionnaire scores for distance, speed, and stair climbing; and the 36-Item Short-Form Health Survey physical functioning score. The results were adjusted for study site, baseline 6-minute walk distance, randomization to exercise vs attention control, sex, and history of heart failure at baseline., Results: Of the 114 randomized patients (mean age, 67.3 [SD, 9.9] years; 46 were women [40.4%]; and 81 were Black individuals [71.1%]), 105 (92%) completed 6-month follow-up. At 6-month follow-up, telmisartan did not significantly improve 6-minute walk distance (from a mean of 341.6 m to 343.0 m; within-group change: 1.32 m) compared with placebo (from a mean of 352.3 m to 364.8 m; within-group change: 12.5 m) and the adjusted between-group difference was -16.8 m (95% CI, -35.9 m to 2.2 m; P = .08). Compared with placebo, telmisartan did not significantly improve any of the 5 secondary outcomes. The most common serious adverse event was hospitalization for PAD (ie, lower extremity revascularization, amputation, or gangrene). Three participants (5.1%) in the telmisartan group and 2 participants (3.6%) in the placebo group were hospitalized for PAD., Conclusions and Relevance: Among patients with PAD, telmisartan did not improve 6-minute walk distance at 6-month follow-up compared with placebo. These results do not support telmisartan for improving walking performance in patients with PAD., Trial Registration: ClinicalTrials.gov Identifier: NCT02593110.

Background: Guidelines recommend measuring blood pressure (BP) in both arms, adopting the higher arm readings for diagnosis and management. Data to support this recommendation are lacking. We evaluated associations of higher and lower arm systolic BPs with diagnostic and treatment thresholds, and prognosis in hypertension, using data from the Inter-arm Blood Pressure Difference-Individual Participant Data Collaboration., Methods: One-stage multivariable Cox regression models, stratified by study, were used to examine associations of higher or lower reading arm BPs with cardiovascular mortality, all-cause mortality, and cardiovascular events, in individual participant data meta-analyses pooled from 23 cohorts. Cardiovascular events were modelled for Framingham and atherosclerotic cardiovascular disease risk scores. Model fit was compared throughout using Akaike information criteria. Proportions reclassified across guideline recommended intervention thresholds were also compared., Results: We analyzed 53 172 participants: mean age 60 years; 48% female. Higher arm BP, compared with lower arm, reclassified 12% of participants at either 130 or 140 mm Hg systolic BP thresholds (both P< 0.001). Higher arm BP models fitted better for all-cause mortality, cardiovascular mortality, and cardiovascular events (all P <0.001). Higher arm BP models better predicted cardiovascular events with Framingham and atherosclerotic cardiovascular disease risk scores (both P <0.001) and reclassified 4.6% and 3.5% of participants respectively to higher risk categories compared with lower arm BPs)., Conclusions: Using BP from higher instead of lower reading arms reclassified 12% of people over thresholds used to diagnose hypertension. All prediction models performed better when using the higher arm BP. Both arms should be measured for accurate diagnosis and management of hypertension., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: CRD42015031227.

An epidemiological transition in the prevalence of peripheral artery disease (PAD) is taking place especially in low- and middle-income countries (LMICs) where an ageing population and adoption of western lifestyles are associated with an increase in PAD. We discuss the limited evidence which suggests that infection, potentially mediated by inflammation, may be a risk factor for PAD, and show by means of an ecological analysis that country-level prevalence of the major endemic infections of HIV, tuberculosis and malaria are associated with the prevalence of PAD. While further research is required, we propose that scientists and health authorities pay more attention to the interplay between communicable and non-communicable diseases, and we suggest that limiting the occurrence of endemic infections might have some effect on slowing the epidemiological transition in PAD., (© 2022. The Author(s).)

Background In people with peripheral artery disease, post hoc analyses of the LITE (Low Intensity Exercise Intervention in Peripheral Artery Disease) randomized trial were conducted to evaluate the effects of walking exercise at a pace inducing ischemic leg symptoms on walking velocity and the Short Physical Performance Battery, compared with walking exercise without ischemic leg symptoms and compared with a nonexercising control group. Methods and Results Participants with peripheral artery disease were randomized to: home-based walking exercise that induced ischemic leg symptoms; home-based walking exercise conducted without ischemic leg symptoms; or a nonexercising control group for 12 months. Outcomes were change of walking velocity over 4 m and change of the Short Physical Performance Battery (0-12, with 12=best) at 6- and 12-month follow-up. A total of 264 participants (48% women, 61% Black race) were included. Compared with walking exercise without ischemic symptoms, walking exercise that induced ischemic symptoms improved change in usual-paced walking velocity over 4 m at 6-month (0.056 m/s [95% CI, 0.019-0.094 m/s]; P <0.01) and 12-month follow-up (0.084 m/s [95% CI, 0.049-0.120 m/s]; P <0.01), change in fast-paced of walking velocity over 4 m at 6-month follow-up ( P =0.03), and change in the Short Physical Performance Battery at 12-month follow-up (0.821 [95% CI, 0.309-1.334]; P <0.01). Compared with control, walking exercise at a pace inducing ischemic symptoms improved change in usual-paced walking velocity over 4 m at 6-month follow-up (0.066 m/s [95% CI, 0.021-0.111 m/s]; P <0.01). Conclusions In people with peripheral artery disease, those who walked for exercise at a comfortable pace without ischemic leg symptoms slowed their walking speed during daily life and worsened the Short Physical Performance Battery score, a potentially harmful effect, compared with people who walked for exercise at a pace inducing ischemic leg symptoms. Compared with a control group who did not exercise, home-based walking exercise at a pace inducing ischemic leg symptoms significantly improved change of walking velocity over 4 m at 6-month follow-up, but this benefit did not persist at 12-month follow-up. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02538900.

Objective: An individual's understanding of disease risk factors and outcomes is important for the ability to make healthy lifestyle choices and decisions about disease treatment. Peripheral artery disease (PAD) is a condition with increasing global prevalence and high risk of adverse patient outcomes. This study seeks to understand the adequacy of disease understanding in patients with PAD., Methods: This was an observational study of patients with PAD recruited from vascular surgery outpatient clinic and PAD clinical studies at a single academic medical center over an 8-month period. A 44-item paper survey assessed demographic and socioeconomic information, knowledge of personal medical history, PAD risk factors, consequences of PAD, and health education preferences. Patients with documented presence of PAD were offered the survey. Patients unable to complete the survey or provide informed consent were not considered eligible. Disease "awareness" was defined as correct acknowledgement of the presence or absence of a disease, including PAD, in the personal medical history. "PAD knowledge score" was the percentage of correct responses to questions on general PAD risk factors and consequences. Of 126 eligible patients, 109 participated. Bivariate analysis was used to study factors associated with awareness of PAD diagnosis. Factors associated with the PAD knowledge score were studied using the Pearson correlation coefficient, two-sample t test, or one-way analysis of variance. P value < .05 was considered statistically significant., Results: The mean participant age was 69.4 ± 11.0 years, and 39.4% (n = 43) were female. Most participants (78.9%; n = 86) had critical limb-threatening ischemia. Only 65.4% (n = 70) of participants were aware of a diagnosis of PAD, which was less than their awareness of related comorbidities. Factors positively associated with PAD diagnosis awareness were female sex (81.4% vs 54.7%; P = .004) and history of percutaneous leg revascularization (78.6% vs 47.9%; P = .001). Among 17 patients who had undergone major leg amputation, 35% (n = 6) were unaware of a diagnosis of PAD. PAD knowledge scores correlated positively with an awareness of PAD diagnosis (59.1% vs 48.7%; P = .02) and negatively with a history of hypertension (53.4% vs 68.1%; P = .001). Most participants (86.5%; n = 90) expressed a desire to be further educated on PAD. The most popular education topics were dietary recommendations, causes, and treatment for PAD., Conclusions: Patients with PAD have deficits in their awareness of this diagnosis and general knowledge about PAD. Future research priorities should further define these deficits and their causes in order to inform new strategies that foster information-seeking behavior and effective educational programs for PAD., (Copyright © 2021 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background Lower ankle-brachial index (ABI) values within the 0.90 to 1.40 range are associated with poorer mitochondrial oxidative capacity of thigh muscles in cross-sectional analyses. Whether ABI decline is associated with greater declines in thigh muscle oxidative capacity with aging is unknown. Method and Results We analyzed data from 228 participants (100 men) of the BLSA (Baltimore Longitudinal Study of Aging), aged 39 to 97 years, with an ABI between 0.9 and 1.40 at baseline and at follow-up (mean follow-up period of 2.8 years). We examined mitochondrial oxidative capacity of the left thigh muscle, by measuring the postexercise phosphocreatine recovery rate constant ( k PCr) from phosphorus-31 magnetic resonance spectroscopy. Greater k PCr indicated higher mitochondrial oxidative capacity. Although k PCr was available on the left leg only, ABI was measured in both legs. Longitudinal rates of change ( Change ) of left and right ABI and k PCr of the left thigh muscle were estimated using linear mixed effects models, and their association was analyzed by standardized multiple linear regressions. In multivariate analysis including sex, age, baseline k PCr, both left and right baseline ABI, and ABI change in both legs, ( k PCr) Change was directly associated with ipsilateral (left) (ABI) Change (standardized [STD]-β=0.14; P =0.0168) but not with contralateral (right) (ABI) Change ( P =0.22). Adjusting for traditional cardiovascular risk factors, this association remained significant (STD-β=0.18; P =0.0051). ( k PCr) Change was steeper in White race participants (STD-β=0.16; P =0.0122) and body mass index (STD-β=0.13; P =0.0479). There was no significant association with current smoking status ( P =0.63), fasting glucose ( P =0.28), heart rate ( P =0.67), mean blood pressure ( P =0.78), and low-density lipoprotein ( P =0.75), high-density lipoprotein ( P =0.82), or triglycerides ( P =0.15). Conclusions In people without peripheral arterial disease, greater decline in ABI over time, but not baseline ABI, was associated with faster decline in thigh mitochondrial oxidative capacity in the ipsilateral leg. Further studies are needed to examine whether early interventions that improve lower extremity muscle perfusion can improve and prevent the decline of muscle energetics.

Patient-reported outcome measures (PROMs) are health outcomes directly reported by the patient that can be used to measure the effect of disease and treatments on patient perceived well-being. This review summarizes current evidence regarding the validation of PROMs in people with symptomatic, nonlimb-threatening peripheral artery disease. A literature search was conducted to identify studies of symptomatic peripheral artery disease without limb-threatening ischemia that included PROMs and had sample sizes ≥25. PROMs were summarized along a continuum of validation using classical test theory framework and according to whether they fulfilled defined criteria for (1) content validity; (2) psychometric validation; and (3) further validation evidence base expansion. Of 2198 articles identified, 157 (7.1%) met inclusion criteria. Twenty-four PROMs in patients with symptomatic peripheral artery disease were reviewed. Among disease-specific PROMs, 8 of 15 had excellent reliability as measured by a Cronbach alpha ≥0.80. Based on established criteria for PROM responsiveness, 6 of 15 disease-specific PROMs demonstrated excellent sensitivity to change. Of these, the disease-specific peripheral artery questionnaire, vascular quality of life questionnaire, and walking impairment questionnaire met criteria for validation at each stage of the continuum. For generic (nondisease specific) PROMs, the European Quality of Life 5-Dimension and SF-36 had the most extensive evidence of validation. Evidence from this review can inform selection of PROMs aligned with scientific and clinical goals, given the variable degree of validation and potential complementary nature of the measures.

Background Associations of 1-year change in functional performance measures with subsequent mobility loss and mortality in people with lower extremity peripheral artery disease are unknown. Methods and Results Six-minute walk and 4-meter walking velocity (usual and fastest pace) were measured at baseline and 1 year later in 612 people with peripheral artery disease (mean age 71±9 years, 37% women). Participants were categorized into tertiles, based on 1-year changes in walking measures. Cox proportional hazards models were used to examine associations between 1-year change in each walking measure and subsequent mobility loss and mortality, respectively, adjusting for potential confounders. Compared with the best tertile, the worst tertile (ie, greatest decline) in 1-year change in each performance measure was associated with higher rates of mobility loss: 6-minute walk (Tertile 1 [T1] cumulative incidence rate [IR], 72/160; Tertile 3 [T3] IR, 47/160; hazard ratio [HR], 2.35; 95% CI, 1.47-3.74), usual-paced 4-meter walking velocity (T1 IR, 54/162; T3 IR, 57/162; HR, 2.21; 95% CI, 1.41-3.47), and fast-paced 4-meter walking velocity (T1 IR, 61/162; T3 IR, 58/162; HR, 1.81; 95% CI, 1.16-2.84). Compared with the best tertile, the worst tertiles in 1-year change in 6-minute walk (T1 IR, 66/163; T3 IR, 54/163; HR, 1.61; 95% CI, 1.07-2.43) and fast-paced 4-meter walking velocity (T1 IR, 63/166; T3 IR, 44/166; HR, 1.75; 95% CI, 1.16, 2.64) were associated with higher mortality. Conclusions In people with peripheral artery disease, greater 1-year decline in 6-minute walk or 4-meter walking velocity may help identify people with peripheral artery disease at highest risk for mobility loss and mortality.

Background Data are sparse on the prospective associations between physical activity and incidence of lower extremity peripheral artery disease (PAD). Methods and Results Linking participant data from the CCLS (Cooper Center Longitudinal Study) to Medicare claims files, we studied 19 023 participants with objectively measured midlife cardiorespiratory fitness through maximal effort on the Balke protocol who survived to receive Medicare coverage between 1999 and 2009. The study aimed to determine the association between midlife cardiorespiratory fitness and incident PAD with proportional hazards intensity models, adjusted for age, sex, body mass index, and other covariates, to PAD failure time data. During 121 288 person-years of Medicare follow-up, we observed 805 PAD-related hospitalizations/procedures among 19 023 participants (21% women, median age 50 years). Lower midlife fitness was associated with a higher rate of incident PAD in patients aged 65 years and older (low fit [quintile 1]: 11.4, moderate fit [quintile 2 to 3]: 7.8, and high fit [quintile 4 to 5]: 5.7 per 1000 person years). After multivariable adjustment for common predictors of incident PAD such as age, body mass index, hypertension, and diabetes, these findings persisted. Lower risk for PAD per greater metabolic equivalent task of fitness was observed (hazard ratio [HR], 0.93 [95% CI, 0.90-0.97]; P <0.001). Among a subset of patients with an additional fitness assessment, each 1 metabolic equivalent task increase from baseline fitness was associated with decreased risk of incident PAD (HR, 0.90 [95% CI, 0.82-0.99]; P =0.03). Conclusions Cardiorespiratory fitness in healthy, middle-aged adults is associated with lower risk of incident PAD in later life, independent of other predictors of incident PAD.

Background: Elevated interleukine-6 (IL-6) and C-reactive protein (CRP) are associated with aging-related reductions in physical function, but little is known about their independent and combined relationships with major mobility disability (MMD), defined as the self-reported inability to walk a quarter mile., Methods: We estimated the absolute and relative effect of elevated baseline IL-6, CRP, and their combination on self-reported MMD risk among older adults (≥68 years; 59% female) with slow gait speed (<1.0 m/s). Participants were MMD-free at baseline. IL-6 and CRP were assessed using a central laboratory. The study combined a cohort of community-dwelling high-functioning older adults (Health ABC) with 2 trials of low-functioning adults at risk of MMD (LIFE-P, LIFE). Analyses utilized Poisson regression for absolute MMD incidence and proportional hazards models for relative risk., Results: We found higher MMD risk per unit increase in log IL-6 (hazard ratio [HR] = 1.26; 95% confidence interval [95% CI] 1.13-1.41). IL-6 meeting predetermined threshold considered to be high (>2.5 pg/mL) was similarly associated with higher risk of MMD (HR = 1.31; 95% CI 1.12-1.54). Elevated CRP (CRP >3.0 mg/L) was also associated with increased MMD risk (HR = 1.38; 95% CI 1.10-1.74). The CRP effect was more pronounced among participants with elevated IL-6 (HR = 1.62; 95% CI 1.12-2.33) compared to lower IL-6 levels (HR = 1.19; 95% CI 0.85-1.66)., Conclusions: High baseline IL-6 and CRP were associated with an increased risk of MMD among older adults with slow gait speed. A combined biomarker model suggests CRP was associated with MMD when IL-6 was elevated., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Supervised exercise therapy (SET) improves walking ability in people with peripheral artery disease (PAD). However, the effects of SET on cardiovascular health in PAD remain unclear. Using data from a randomized clinical trial, this post hoc analyses investigated the effects of a 6-month SET intervention, compared with a control group, on changes in blood pressure (BP) and heart rate (HR) during a graded treadmill exercise test in people with PAD., Methods: We randomized 210 participants with PAD to either SET (3× weekly) or control (1× weekly health lectures) for 6 months. A graded treadmill exercise test, 6-minute walk test, and Walking Impairment Questionnaire were completed at baseline and the 6-month follow-up. BP and HR were measured at the end of each 2-minute stage of the graded treadmill exercise test. Mixed effects regression models compared the overall mean 6-month change in systolic BP, diastolic BP, pulse pressure (PP), and HR during the first 5 stages of the graded treadmill exercise test between groups., Results: Of the 210 randomized participants with PAD, 176 (67 ± 9 years; 72 [41%] female, 115 [65%] Black) completed the graded treadmill exercise test at baseline and the 6-month follow-up. Compared with the control group at the 6-month follow-up, SET significantly decreased overall mean systolic BP (-12 mm Hg; P < .001), PP (-9 mm Hg; P < .001), and HR (-7 b/min; P < .01) during a graded treadmill exercise test but not diastolic BP. Among participants randomized to SET, a greater decrease in systolic BP, PP, and HR during a graded treadmill exercise test was significantly associated with a greater improvement in 6-minute walk distance (systolic BP, r = -0.19 [P = .03] and PP, r = -0.23 [P < .01]; and HR, r = -0.21 [P < .01]) and with maximal treadmill walking distance (systolic BP, r = -0.21 [P < .01] and PP, r = -0.17 [P = .03]) at the 6-month follow-up. A greater decrease in the HR during a graded treadmill exercise test was significantly associated with a better WIQ distance score (r = -0.27; P = .03) at the 6-month follow-up., Conclusions: In people with PAD, compared with a control group, SET improved cardiovascular health, measured by changes in BP and HR during exercise. The degree of improvement in cardiovascular health correlated with the degree of improvement in walking performance in people with PAD. NCT: 01408901., (Copyright © 2021. Published by Elsevier Inc.)

Competing Interests: Funding Support and Author Disclosures Dr Kusumoto is Chair of the Peer Review Task Force; Chair-elect of the American College of Cardiology (ACC) Scientific Publications Committee; and President of the Heart Rhythm Society. Dr Bittl is a member of the ACC Scientific Publications Committee. Dr Creager is a member of the ACC Scientific Publications Committee. Dr Dauerman is an Associate Editor of the Journal of the American College of Cardiology; and has received research funding from and served as a consultant to Medtronic and Boston Scientific. Dr Lala is Deputy Editor of the Journal of Cardiac Failure; and has received speaker honoraria from Zoll Medical and Abbott. Dr McDermott is Deputy Editor of the Journal of the American Medical Association; has received research funding from Regeneron; and has received other research support from Helixmith, ArtAssist, Hershey, Mars, Chromadex, and ResearveAge. Mrs Varieur Turco is Divisional Senior Director of Publishing, ACC. Dr Taqueti is Chair of the ACC Scientific Publications Committee.

This study investigated cross-sectional associations of peripheral artery disease (PAD) severity (defined by the ankle-brachial index (ABI)) and amounts of daily sustained physical activity (PA) (defined as > 100 activity counts per minute lasting 5 consecutive minutes or more). This study also investigated associations of amounts of daily sustained PA with 6-minute walk (6MW) distance and the Short Form-36 physical functioning domain (SF-36 PF) score in cross-sectional analyses and with serious adverse events (SAEs) in longitudinal analyses of people with PAD. PA was measured continuously for 10 days using a tri-axial accelerometer at baseline in 277 participants with PAD randomized to the LITE clinical trial. In regression analyses, each 0.15 lower ABI value was associated with a 5.67% decrease in the number of daily bouts of sustained PA (95% CI: 3.85-6.54; p < 0.001). Every additional bout of sustained PA per day was associated with a 4.56-meter greater 6MW distance (95% CI: 2.67-6.46; p < 0.0001), and a 0.81-point improvement in SF-36 PF score (95% CI: 0.34-1.28; p < 0.001). Participants with values of daily bouts of sustained PA below the median had higher rates of SAEs during follow-up, compared to participants above the median (41% vs 24%; p = 0.002). In conclusion, among participants with PAD, lower ABI values were associated with fewer bouts of daily sustained PA. A greater number of bouts of daily sustained PA were associated with better 6MW performance and SF-36 PF score, and, in longitudinal analyses, lower rates of SAEs. Clinicaltrials.gov ID: NCT02538900.

Lower extremity peripheral artery disease (PAD) affects >230 million adults worldwide and is associated with increased risk of various adverse clinical outcomes (other cardiovascular diseases such as coronary heart disease and stroke and leg outcomes such as amputation). Despite its prevalence and clinical importance, PAD has been historically underappreciated by health care professionals and patients. This underappreciation seems multifactorial (eg, limited availability of the first-line diagnostic test, the ankle-brachial index, in clinics; incorrect perceptions that a leg vascular disease is not fatal and that the diagnosis of PAD would not necessarily change clinical practice). In the past several years, a body of evidence has indicated that these perceptions are incorrect. Several studies have consistently demonstrated that many patients with PAD are not receiving evidence-based therapies. Thus, this scientific statement provides an update for health care professionals regarding contemporary epidemiology (eg, prevalence, temporal trends, risk factors, and complications) of PAD, the present status of diagnosis (physiological tests and imaging modalities), and the major gaps in the management of PAD (eg, medications, exercise therapy, and revascularization). The statement also lists key gaps in research, clinical practice, and implementation related to PAD. Orchestrated efforts among different parties (eg, health care providers, researchers, expert organizations, and health care organizations) will be needed to increase the awareness and understanding of PAD and improve the diagnostic approaches, management, and prognosis of PAD.