Background: Poor physical function is common in chronic kidney disease (CKD) and is associated with adverse outcomes; however, patterns of impairment are heterogeneous, and underlying mechanisms remain poorly understood. Traditional single-variable classification approaches may not fully capture this heterogeneity, potentially missing distinct at-risk subgroups. Hypothesis: We hypothesized that pattern-based phenotyping would identify clinically meaningful subgroups with different physiological profiles. Methods: Patients with CKD stage 3-4 (n=72, 62± 9 yr, 78% male, eGFR: 45±13 ml/min/1.73m 2 ) completed a 4-domain physical function assessment (handgrip strength, gait speed, chair-stand time, and static balance), body composition and volume status (extracellular water/total body water (ECW/TBW)) by bioimpedance, and vascular stiffness (pulse pressure, augmentation index (AIx). Hierarchical clustering was applied to z-standardized 4-domain for physical function scores to identify multi-variable patterns. Construct validity was evaluated through Spearman correlations and principal components analysis (PCA). To further characterize phenotypes, the associations between individual physical functional measures and clinical risk factors were assessed. Results: Three phenotype clusters emerged; 1) High-functioning (n=38, 53%, 60± 9 yr, 18% female) demonstrated better performance across all functional domains compared to other clusters (p< 0.05); 2) Lower-limb Mobility Impairment (n=6, 8.3%, 54± 15 yr, 17% female) exhibited markedly slower chair-stand performance (p< 0.05) with preserved gait and balance, relatively to the High-functioning; 3) Multi-domain Impairment (n=28, 39%, 66±6 yr, 29% female) showed reduced performance across all domains (p< 0.05 for all), with the older age (p=0.006), elevated pulse pressure (p=0.024), ECW/TBW (p=0.017) and albumin-to-creatine ratio (p=0.059) and reduced skeletal muscle mass percent (p=0.067), compared to the High-functioning. Functional measures demonstrated distinct constructs (Spearman correlations: all |r|< 0.4). PCA revealed two components explaining 74% of variance: PC1 (47%, general function) and PC2 (27%, mobility vs. stability). Grip strength was associated with age, skeletal muscle mass percent, pulse pressure, AIx, ECW/TBW; gait speed with ECW/TBW (p< 0.001 for all); balance with age (p=0.003) and pulse pressure. Conclusion: Pattern-based phenotyping identified distinct physical function phenotypes in CKD with different clinical profiles. While the High-functioning phenotype maintained functional capacity across all domains, the Multi-domain Impairment phenotype displayed global functional deficits accompanied by volume overload, vascular dysfunction, and low muscle mass. The Lower-limb Mobility Impairment phenotype exhibited domain-specific dysfunction ofimpaired lower-extremity power despite preserved gait speed and balance, representing a dissociation pattern undetectable by single-variable classification. Pattern-based multi-domain assessment provides comprehensive characterization of physical function profiles in CKD and may inform targeted intervention strategies. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Arterial endothelial cells (ECs) reside in a complex biomechanical environment. ECs sense and respond to wall shear stress. Low and oscillatory wall shear stress is characteristic of disturbed flow and commonly found at arterial bifurcations and around atherosclerotic plaques. Disturbed flow is pro-inflammatory to ECs. Arteries also stiffen with aging and/or the onset of vascular disease. ECs sense and respond to stiffening in a pro-fibrotic manner. Thus, flow and stiffening disturbances elicit EC responses that promote pathologic arterial remodeling. However, the pathways elicited by ECs under pathologic stiffening and disturbed flow are not well understood. The objective of this work was to discover and test the modifiability of key pathways in ECs. To do this we used the partial carotid ligation model to impose disturbed flow onto the precociously stiffened fibulin-5 knockout (Fbln5-/-) mouse carotid arteries. Biomechanical testing demonstrated that Fbln5-/- arteries under disturbed flow approximate the stiffness ratio of diseased human arteries, and the ECs in these Fbln5-/- arteries underwent rapid reprogramming via endothelial to mesenchymal transition (EndMT). Under atherogenic conditions, disturbed flow Fbln5-/- arteries developed more vulnerable plaques than the wild type (WT) mouse arteries. Connective tissue growth factor/cellular communication network factor 2 (Ctgf/Ccn2) was upregulated in vivo in ECs with aging, with stiffening in the Fbln5-/- arteries, and increased again by disturbed flow under stiffened conditions, supporting CTGF as a key biomarker for flow and stiffening. This was validated by immunohistochemistry, which demonstrated increased CTGF deposition in areas of disturbed flow in patient carotid endarterectomy and peripheral artery disease (PAD) specimens. Finally, to test the role of CTGF in regulating and combining these processes, we created an EC-specific Ctgf knockout (Ctgfecko). We identified that carotid arteries under disturbed flow and atherogenic conditions in male Ctgfecko, but not female, mice had decreased plaque area compared to WT control mice. We then tested the Ctgf expression in the carotid endothelium exposed to disturbed or stable flow in WT and Fbln5-/- mice. Here we found that under disturbed flow male mice had greater Ctgf expression than female mice. This work demonstrates that stiffened + disturbed flow conditions drive EC reprogramming, that CTGF is increased by these conditions, and that this increase is more prominent in male carotid arteries. Future exploration of sex-based differences in these fibrotic pathways are warranted to develop targeted therapeutics to limit pathologic arterial remodeling under pathologically stiffened + disturbed flow environments.

Purpose:This study investigated the long-term progression of oscillatory potential (OP) implicit times (ITs) in individuals with preclinical diabetic retinopathy (DR) with and without levodopa (L-DOPA) treatment by quantifying functional and structural retinal changes. Methods:Participants from the Motz et al. (2020) study were re-evaluated after 5 years, including individuals with diabetes mellitus (DM) who received L-DOPA treatment for 2 weeks (the DM + L-DOPA group; n = 14), those who did not (the DM group; n = 6), and non-diabetic healthy controls (the control group; n = 37). Retinal function and structure were assessed using dim-flash electroretinography (ERG) and optical coherence tomography (OCT). Results:After 5 years, OP 1 and OP 2 ITs showed no significant differences among the groups (P > 0.05). The DM + L-DOPA OP IT values remained improved compared to baseline. The outer region thickness of the outer plexus layer (OPL) and ganglion cell layer (GCL) were significantly thinner in the DM + L-DOPA group compared to the DM group (P < 0.05). The DM group showed strong correlations between OP IT and OCT thickness across all retinal regions, whereas the DM + L-DOPA group correlations were similar to the control group. Conclusions:Short-term L-DOPA treatment led to significant functional improvements after 2 weeks, with trends suggesting sustained benefit over 5 years. Inner retinal structural differences suggest potential long-term benefit of L-DOPA on retinal health. These findings support OP IT delays as early biomarkers for preclinical DR and suggest L-DOPA may provide lasting neuroprotective benefits. Translational Relevance:Retinal dysfunction and inner retinal structural changes could be potential biomarkers for preclinical DR, and L-DOPA treatment may provide sustained benefits for the diabetic retina.

Objective: The mechanisms of structured exercise therapy (SET) in peripheral artery disease (PAD) are not clear. We have developed an SET module for our large animal model of ischemic myopathy. We hypothesized that SET would increase muscle strength and walking distance in this model. The objective was to discover the SET-dependent mechanisms involved in this process.Approach: After induction of unilateral hind limb ischemia, three animals were exposed to standard environmental enrichment (sedentary or SED) and four animals underwent SET thrice weekly for 4 weeks postoperatively. Walking, hind limb pressure indices, and strength testing were performed weekly. Terminal muscle samples were used for skeletal muscle testing.Results: SET animals increased walking distance over time. SET increased muscle strength in both the ischemic and nonischemic limb. When comparing the ischemic SED hind limb muscle with that of ischemic + SET, the SET group has improved respiration and decreased oxidative stress. Markers of cell death and impaired functional regeneration were increased in SED ischemic muscles but returned toward baseline in the SET ischemic muscle.Innovation: This study uses a validated, large animal model of ischemic myopathy similar to that seen in humans with PAD. The effects of exercise on limb function, strength, and skeletal muscle health are reported in this model.Conclusion: SET increases muscle strength and regeneration by increasing endogenous antioxidants and mitochondrial respiration, resulting in favorable muscle health despite ongoing ischemia. This model may assist in preclinical testing of PAD therapies designed to improve muscle health.

Objective: The objectives of this work are to: define murine femoral artery stiffening with age and the modifiability of this process by exercise; impose peripheral arterial disease (PAD) hemodynamics on murine femoral arteries and to deliver focal atherosclerotic plaque to femoral arteries; and test piezo-type mechanosensitive ion channel component 1 (PIEZO1) expression in human and murine femoral arteries of PAD. Methods: We used a running wheel to exercise young and old S129 mice and biomechanical testing to quantify changes in arterial stiffness. We created a novel partial femoral artery ligation (PFL) model to impose PAD hemodynamics via low wall shear stress (WSS) to create a flow-mediated model of arterial aging in femoral arteries. In vivo mechanics were defined with ultrasound. Ex vivo arteries underwent biaxial tests. Atherogenic conditions were induced using PCSK9 infection and a high-fat diet. Arterial remodeling and PIEZO1 expression were quantified by histology. Results: Femoral arteries are naturally stiffer than carotid arteries; both stiffen further with aging, but exercise improved compliance in old femoral arteries. PFL imposed low WSS and stiffening, similar to that seen in aging. Under atherogenic conditions, PFL delivered focal atherosclerotic plaques in femoral arteries. Low WSS increased PIEZO1 expression in femoral arteries (∼1.8× in endothelial cells, ∼2.4× in smooth muscle cells, and ∼2.8× in macrophages). Human PAD arteries with high-grade stenosis validated increased PIEZO1 mRNA (∼1.83×). Conclusions: Femoral artery mechanics differ significantly from the carotid artery but can be modified by exercise. This PFL model confers arterial stiffness, and under atherogenic conditions, delivers focal femoral atherosclerotic plaque. PIEZO1 expression increases in both PFL-treated mouse femoral arteries and human PAD arteries with severe stenosis, supporting this as a translational target for PAD. Clinical Relevance: Peripheral artery disease (PAD) is the third most common atherosclerotic bed. PAD is associated with increased risk of limb loss and death, but the mechanisms driving site-specific arterial remodeling in PAD remain unclear. This work uniquely creates a model of PAD that incorporates arterial stiffening via aging and flow disturbances and inducing atherosclerotic plaque into the murine femoral artery. By comparing murine femoral arteries with PAD arteries, piezo-type mechanosensitive ion channel component 1 (PIEZO1) was discovered as key mediator linking PAD blood flow and stiffening to untoward changes in endothelial cells, smooth muscle cells, and macrophages within femoral arteries. Targeted modulation of PIEZO1 activity provide PAD-centric therapeutic strategies and help promote the vascular health, life, and limb outcomes in patients with PAD.

Key PointsSodium-glucose cotransporter-2 inhibitor (SGLT2i) use has not been extensively studied in autosomal dominant polycystic kidney disease (ADPKD).In veterans with ADPKD, kidney function declined at a greater rate during the first 3 months post-SGLT2i initiation but subsequently attenuated.In veterans with ADPKD, SGLT2i versus dipeptidyl peptidase-4 inhibitor use was associated with slower long-term kidney function decline.BackgroundSodium-glucose cotransporter-2 inhibitors (SGLT2is) are a pillar of kidney disease therapy, but their efficacy remains unknown in autosomal dominant polycystic kidney disease (ADPKD). We evaluated effects of SGLT2i on kidney function in ADPKD.MethodsThis retrospective cohort study within the Veterans Health Administration included adults with an ADPKD diagnosis code who initiated SGLT2i between January 2017 and May 2023. Repeated measures models were used to evaluate eGFR slope before and after SGLT2i initiation. Among patients with ADPKD and type 2 diabetes mellitus, a target trial emulation was used to compare the effects of SGLT2i versus dipeptidyl peptidase-4 inhibitor (DPP4i) on eGFR slope.ResultsAmong 348 eligible patients with ADPKD who started an SGLT2i, 93% were male, mean +/- SD age was 68 +/- 11, and median eGFR was 53 (interquartile range: 16-127) ml/min per 1.73 m2. In adjusted analyses, the preinitiation eGFR slope was -0.79 (95% confidence interval, -1.26 to -0.33) ml/min per 1.73 m2 per 90 days. The eGFR slope steepened to -2.78 (-4.04 to -1.53) ml/min per 1.73 m2 during the first 3 months postinitiation and then stabilized to -0.07 (-0.72 to 0.58) ml/min per 1.73 m2 during months 3-12 postinitiation. The target trial emulation compared 217 SGLT2i users with 198 DPP4i users. In adjusted analyses, eGFR declined -4.03 (-6.45 to -1.60) ml/min per 1.73 m2 per 90 days faster in SGLT2i users versus DPP4i users during the first 3 months postinitiation; however, during the subsequent 3-12 months, the slope was more stable in SGLT2i initiators than DPP4i initiators, with a difference of 1.29 (0.16 to 2.41) ml/min per 1.73 m2 per 90 days.ConclusionsIn older patients with mild ADPKD and a high prevalence of diabetes and cardiovascular disease who initiated an SGLT2i, there was an initial 3-month decline in eGFR followed by stabilization during the remainder of the year-long follow-up. Compared with DPP4i use, SGLT2i use was associated with a slower eGFR decline between 3 and 12 months postinitiation in patients with concurrent type 2 diabetes mellitus. These findings suggest that SGLT2is are potentially beneficial in older individuals with ADPKD in whom comorbid disease may play a greater role in kidney function decline, but further studies are required.

Background We used the largest integrated US healthcare system, the Veterans Health Administration, to establish a robust resource for demographic, longitudinal outcome, and predictive modeling studies in autosomal dominant polycystic kidney disease (ADPKD). Methods We built the ADPKD cohort by extracting the relevant electronic health record data from nationwide Veterans Health Administration database (years 1999-2020). Results We identified 12,217 patients diagnosed with ADPKD. By the end of the 20-year study period, 5342 patients with ADPKD were deceased, 1583 were alive but reached ESKD, and 4827 remained alive without ESKD. Most demographic characteristics of this ADPKD cohort resemble the total US veteran population. For example, 94% were male patients, 45% age 65 years or older, 85% non-Hispanic, and 66% white; however, 19% were Black/African Americans (versus 12% in the general veteran population; a relevant enrichment after considering age and sex distributions between races). The comorbidities overrepresented in the ADPKD cohort include hypertension (89% versus 50%), diabetes (32% versus 22%), depression (40% versus 10%), chronic obstructive pulmonary disease (30% versus 6%), and congestive heart failure (21% versus 1%). By contrast, obesity was underrepresented in veterans with ADPKD (30% versus 41%). Conclusions We established a large electronic medical record-based cohort of ADPKD veterans. Here, we provide initial analysis of its demographic, comorbidity, and key laboratory data.

Introduction: Inflammation is a significant contributor to cardiovascular disease (CVD) in people with HIV (PWH), who face twice the risk of CVD compared to the general population. The presence of co-existing rheumatic disease (RD) may further exacerbate inflammation and increase the incidence of CVD events in this population. Methods: We conducted a retrospective study using electronic health record (EHR) data from the Veterans Affairs Medical Center in Atlanta, covering the period from 2000 to 2019. The study included 3,930 veterans with HIV, and assessed the impact of rheumatic disease therapies (RDT) on CVD outcomes. The primary outcome was the first occurrence of a CVD event. Results: Rheumatic disease was significantly associated with an increased risk of CVD events (OR = 2.67; p < 0.001). Additionally, exposure to multiple RDTs (aHR = 2.121, p = 0.047), NSAIDs (aHR = 1.694, p = 0.003), glucocorticoids (aHR = 2.332, p < 0.0001), and hypouricemic agents and colchicine (aHR = 3.445, p < 0.0001) were all significantly associated with increased CVD events. Conclusion: The co-existence of HIV infection and rheumatic disease, along with the use of RDTs, may amplify the risk of CVD events in PWH. These findings underscore the need for further investigation into the relationship between RD, RDTs, and CVD risk in larger, controlled studies, given the potential implications for treatment decisions in this patient population.

Our findings identify robust acute kidney injury (AKI)-induced developmental reprogramming of macrophages (MΦ) with the expansion of C1Q + , CD163 + MΦ that is independent of the etiology of AKI and conserved across mouse and human species.

Introduction: Inflammation is a significant contributor to cardiovascular disease (CVD) in people with HIV (PWH), who face twice the risk of CVD compared to the general population. The presence of co-existing rheumatic disease (RD) may further exacerbate inflammation and increase the incidence of CVD events in this population. Methods: We conducted a retrospective cohort study using electronic health record (EHR) data from the Veterans Affairs Medical Center in Atlanta, covering the period from 2000 to 2019. A total of 5000 patients aged 20-87 years who were diagnosed with HIV and receiving care at the Atlanta VAMC between 2000 and 2019 were eligible for this analysis. This study included 3930 veterans with HIV and assessed the impact of rheumatic disease therapies (RDTs) on CVD outcomes. The primary outcome was the first occurrence of a CVD event. Results: Rheumatic disease was significantly associated with an increased risk of CVD events (OR = 2.67; p < 0.001). Additionally, exposure to multiple RDTs (aHR = 2.121, p = 0.047), NSAIDs (aHR = 1.694, p = 0.003), glucocorticoids (aHR = 2.332, p < 0.0001), and hypouricemic agents and colchicine (aHR = 3.445, p < 0.0001) were all significantly associated with increased CVD events. Conclusions: The co-existence of HIV infection and rheumatic disease, along with the use of RDTs, may amplify the risk of CVD events in PWH. These findings underscore the need for further investigation into the relationship between RD, RDTs, and CVD risk in larger, controlled studies, given the potential implications for treatment decisions in this patient population. A limitation of our study is that due to its retrospective design, we could not examine the impact of the sequential use of RDT groups and RD severity on CVD events.

Introduction: Aortic stenosis is the most common valvular heart disease and is managed by aortic valve replacement (AVR) procedures. Comorbid conditions may impact survival after AVR. Methods: We evaluated risk factors for all-cause mortality after AVR in the Veterans Affairs (VA) healthcare system for individuals with an AVR between January 1 st 2007 and December 31 st 2017, with National Death Index mortality data through December 31 st , 2020. Clinical diagnoses and procedures were established by International Classifications of Disease (ICD) and Current Procedural Terminology (CPT) codes both in the VA and the Center for Medicare and Medicaid Services. Hazard rates for the primary outcome of all-cause mortality were calculated using a cox proportional hazards model adjusted for age at AVR, sex, and prevalent clinical risk factors (heart failure [HF], obesity, type 2 diabetes [T2D], and myocardial infarction [MI]). Results: There were 7,984,029 individuals seen regularly at the VA between 2007 and 2017. Within this group, there were 783,772 (9.8%) individuals with an established diagnosis of AS without prior valve replacement with a median (interquartile [IQR]) age of 73.5 [67.4-80.3] years, and 98% male. Between 2007-2017, 66,931 individuals had an AVR with median [IQR] age 72.8 [66.6-79.3] years, 98% male. Of the individuals with an AVR, 24,253 (36.2%) died prior to the end of follow up, with a median [IQR] time to death of 3.3 [2.8-5.3] years. At the time of valve replacement, there were 16,301 (24%) diagnoses of CKD, 11,916 (18%) diagnoses of HF, 21,575 (32%) diagnoses of T2D, and 4,211 (6%) diagnoses of prior MI. In a multivariable model, with adjustment for age, sex, and all clinical risk factors, a prevalent HF diagnosis portended the highest risk of all-cause mortality after AVR (HR 1.57 [1.52-1.62], p < 0.001), followed by T2D (HR 1.13 [1.09-1.16], p < 0.001), CKD (HR 1.11 [1.08-1.15], p < 0.001), and MI (1.05 [0.99-1.11], p = 0.06). Conclusions: Common clinical comorbidities including HF, CKD, and T2D, but not MI independently increase the risk of all-cause mortality after AVR.

Background Peripheral arterial disease (PAD) is the 3rd leading type of atherosclerotic disease (ASD) morbidity. Arterial stiffness is intimately connected to the onset and progression of peripheral artery disease (PAD). The role of arterial stiffening on flow-mediated atherosclerotic plaque formation is not well understood. The objective of this study is to discover endothelial cell (EC) pathways under PAD conditions and test the modifiability of these pathways on ASD. Methods PAD conditions in mice were conferred by partial carotid ligation to induce disturbed Flow (D-flow) in pre-stiffened Fibulin-5 knockout (KO) mice that lack normal elastin function. EC pathways, including Connective tissue growth factor (CTGF/CCN) were quantified by gene analysis and histology. Atherogenic mice had PCSK9 infection + high fat diet. CTGF was inhibited in an EC-specific knockout (ECKOCTGF) and with a CTGF antibody (FG-3149). Human vascular tissue was used to validate PAD biomechanics and CTGF upregulation. Results Biomechanical testing demonstrated that d-flow KO arteries mimic biomechanics of PAD arteries. RNA microarray, qPCR, and immunohistochemistry identified EC plasticity in these arteries compared to WT and KO under stable flow. Under atherogenic conditions, KO arteries demonstrated vulnerable plaques not seen in WT animals. CTGF expression was increased by d-flow, in KO arteries, in aged (18 months) WT arteries, and vascular tissue under d-flow. CTGF inhibition by ECKOCTGF favorably improved plaque characteristics in male but not female animals. FG-3149 treatment of ECWTCTGF male animals delivered similar benefits to plaque characteristics and arterial compliance. Conclusion ECs in PAD arteries exist under a complex hemodynamic environment that integrates stiffness and d-flow into an atherogenic and inflammatory environment. Stiffness + d-flow stimulates precocious onset of EC plasticity and a vulnerable plaque phenotype. CTGF is a matricellular protein that can tune fibro-inflammatory pathways. CTGF is a prominent mediator of D-flow-mediated arterial remodeling and focal atherosclerotic plaque remodeling. Inhibition of CTGF improves plaque phenotype and arterial compliance. CTGF-associated pathways hold promise as therapeutic targets for PAD patients. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by awards from the National Institutes of Health to Drs. Brewster, Gleason, and Jo (HL143348). The authors' work is supported by funding from the NIH grants HL119798, HL139757, and HL151358 (to H.J.). H.J. was also supported by Wallace H. Coulter Distinguished Faculty Professorship. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Not Applicable The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Emory University approved IRB protocol numbers: 51432 and 70813 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Not Applicable I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Not Applicable I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Not Applicable Resource Availability The data that support the findings of this study are available from the corresponding author upon reasonable request. Lead Contact Further information and requests for resources and reagents should be directed to and will be fulfilled by the Lead Contact, Luke Brewster. Materials Availability Further requests for resources and reagents should be directed to and will be fulfilled by the Lead Contact, Luke Brewster. This study did not generate new unique reagents. Data availability The RNA files generated from the study (fibulin-5 KO and WT animals) will be available at the NCBI GEO repository on January 1, 2024, as GEO Submission (accession number GSE222583).

Pathways to which the identified 24 genes downregulated by JQ1 treatment in CCA2 (Figure 5) contribute.

Time course of increase in tumor volume in mice treated with vehicle (VC) or JQ1.

Immunoblot analysis showing that JQ1 downregulates TEK, Chk1, MSH2 and LCK expression in CCA2 tumors, but not in CCA1 tumors.

Importance Patient-level characteristics alone do not account for variation in care among US veterans with peripheral artery disease (PAD). Presently, the extent to which health care utilization and regional practice variation are associated with veterans receiving vascular assessment prior to major lower extremity amputation (LEA) is unknown. Objective To assess whether demographics, comorbidities, distance to primary care, the number of ambulatory clinic visits (primary and medical specialty care), and geographic region are associated with receipt of vascular assessment prior to LEA. Design, Setting, and Participants This national cohort study used US Department of Veterans Affairs’ Corporate Data Warehouse data from March 1, 2010, to February 28, 2020, for veterans aged 18 or older who underwent major LEA and who received care at Veterans Affairs facilities. Exposures The number of ambulatory clinic visits (primary and medical specialty care) in the year prior to LEA, geographic region of residence, and distance to primary care. Main Outcomes and Measures The main outcome was receipt of a vascular assessment (vascular imaging study or revascularization procedure) in the year prior to LEA. Results Among 19 396 veterans, the mean (SD) age was 66.78 (10.20) years and 98.5% were male. In the year prior to LEA, 8.0% had no primary care visits and 30.1% did not have a vascular assessment. Compared with veterans with 4 to 11 primary care clinic visits, those with fewer visits were less likely to receive vascular assessment in the year prior to LEA (1-3 visits: adjusted odds ratio [aOR], 0.90; 95% CI, 0.82-0.99). Compared with veterans who lived less than 13 miles from the closest primary care facility, those who lived 13 miles or more from the facility were less likely to receive vascular assessment (aOR, 0.88; 95% CI, 0.80-0.95). Veterans who resided in the Midwest were most likely to undergo vascular assessment in the year prior to LEA than were those living in other regions. Conclusions and Relevance In this cohort study, health care utilization, distance to primary care, and geographic region were associated with intensity of PAD treatment before LEA, suggesting that some veterans may be at greater risk of suboptimal PAD care practices. Development of clinical programs, such as remote patient monitoring and management, may represent potential opportunities to improve limb preservation rates and the overall quality of vascular care for veterans.