Progression Of Peripheral Arterial Disease Research Articles

Peripheral Arterial Disease in Diabetes and its Relation to Cardiovascular Risk Factors in Women

Objectives: Peripheral arterial disease (PAD) is characterized by occlusive disease in the abdominal aorta, iliac, and femoral arteries, leading to reduced blood flow and complications. Diabetes mellitus (DM) is known to contribute to the development and progression of PAD due to factors such as hyperglycemia, dyslipidemia, endothelial dysfunction, and inflammation. However, PAD may be underdiagnosed in women with DM, leading to adverse cardiovascular outcomes. The present study aimed to investigate the prevalence of PAD in women with type 2 DM (T2DM) and its relationship with cardiovascular risk factors. Materials and Methods: This hospital-based, cross-sectional, and observational study was conducted for a period of 3 months from June 10, 2023, to September 10, 2023, in the outpatient department of general medicine. After obtaining the approval from the Institutional Ethical Committee, the study was performed according to the Declarations of Helsinki and Good Clinical Practice requirements for human subject protection. Non-probability purposive sampling technique was used to enroll participants. Participants underwent face-to-face interviews and clinical examinations. Sociodemographic data, medical history, and pharmacotherapy details were collected. Laboratory investigations were conducted, including blood glucose, lipid profile, and glycosylated hemoglobin (HbA1C) tests. The ankle-brachial index (ABI) was measured. Results: The results showed that the majority of the participants were between 50 and 70 years of age, married, and had a high school education. Participants had an average body mass index (BMI) indicating overweight, and the average duration of diabetes was 6.571 years. Hypertension was the most prevalent comorbidity. Overweight, obesity I, and obesity II were present in 15.25% (n = 19), 33.6% (n = 42), and 8.8% (n = 11), respectively. Average values for HbA1C, fasting blood glucose (FBG), and postprandial blood glucose (PPBG) were within the diabetic range. ABI was normal in the right side, left side, and bilateral in 43.2%, 56%, and 14.4% of participants, respectively. ABI was borderline on the right side, left side, and bilateral in 40.8%, 36.8%, and 22.4% of participants, respectively. PAD was observed on the right side, left side, and bilateral in 16%, 7.2%, and 4% of participants, respectively. BMI, duration of DM, glycosylated hemoglobin, FBG, and PPBG showed significant negative correlations with ABI. Age, triglycerides, high-density lipoprotein, and low-density lipoprotein did not show any statistically significant correlation with ABI. Conclusion: The study highlighted the importance of screening for PAD in women with T2DM to improve cardiovascular outcomes. The findings shed light on the prevalence of risk factors for PAD and their association with the disease. These insights can contribute to the development of targeted interventions to reduce adverse clinical outcomes in this population.

Liraglutide for Lower Limb Perfusion in People With Type 2 Diabetes and Peripheral Artery Disease

Peripheral artery disease (PAD) in diabetes may lead to diabetic foot ulcer and lower-extremities amputation. Glucagon-like peptide 1 receptor agonists have proven cardiovascular benefits in trials of people with type 2 diabetes at high cardiovascular risk. To examine the effect of liraglutide on peripheral perfusion measured as peripheral transcutaneous oxygen pressure (TcPo2) in individuals with type 2 diabetes and PAD. This open-label randomized clinical trial was conducted between February 1, 2021, and June 30, 2022, with a final follow-up on December 30, 2022, at University of Campania "Luigi Vanvitelli," Naples, Italy. Fifty-five individuals with type 2 diabetes, PAD, and TcPo2 between 30 and 49 mm Hg were included. Patients were randomized to receive 1.8 mg of subcutaneous liraglutide or conventional treatment of cardiovascular risk factors (control group) for 6 months. Coprimary outcomes were the change from baseline of peripheral perfusion between groups and the comparison of the proportion of individuals who reached 10% increase of TcPo2 from baseline in each group. Fifty-five participants (mean [SD] age, 67.5 [8.5] years; 43 [78%] male) were randomized (27 to the liraglutide group and 28 to the control group) and analyzed. Participants had a median (IQR) hemoglobin A1c level of 6.9% (6.5%-7.8%) and a mean (SD) TcPo2 of 40.3 (5.7) mm Hg. Transcutaneous Po2 increased over time in both groups, with significant differences favoring the liraglutide group after 6 months (estimated treatment difference, 11.2 mm Hg; 95% CI, 8.0-14.5 mm Hg; P < .001). The 10% increase of TcPo2 occurred in 24 participants (89%) in the liraglutide group and 13 (46%) in the control group (relative risk, 1.91; 95% CI, 1.26-2.90; P < .001). Compared with the control group, individuals in the liraglutide group had a significant reduction of C-reactive protein (-0.4 mg/dL; 95% CI, -0.7 to -0.07 mg/dL; P = .02), urinary albumin to creatinine ratio (-119.4 mg/g; 95% CI, -195.0 to -43.8 mg/g; P = .003), and improvement of 6-minute walking distance (25.1 m; 95% CI, 21.8-28.3 m; P < .001). In this randomized clinical trial of people with type 2 diabetes and PAD, liraglutide increased peripheral perfusion detected by TcPo2 measurement during 6 months of treatment. These results support the use of liraglutide to prevent the clinical progression of PAD in individuals with type 2 diabetes. ClinicalTrials.gov Identifier: NCT04881110.

The Clinical Utility of Lower Extremity Dual-Energy CT Angiography in the Detection of Bone Marrow Edema in Diabetic Patients with Peripheral Artery Disease.

(1) Background: Type 2 diabetes is a major cause of incidences and the progression of peripheral artery disease (PAD). Bone marrow edema (BME) is an important finding suggestive of underlying bone inflammation in non-traumatic diabetic patients with PAD. Our aim was to evaluate the presence, severity, and clinical implications of BME detected by virtual non-calcium application (VNCa) of dual-energy CT angiography (DE-CTA). (2) Methods: A consecutive series of 76 diabetic patients (55 men; mean age 71.6 ± 11.2 yrs) submitted to lower limb DE-CTA for PAD evaluation and revascularization planning, which were retrospectively analyzed. VNCa images were independently and blindly revised for the presence, location, and severity of BME by two radiologists with 10 years of experience. BME and non-BME groups were evaluated in terms of PAD clinical severity and 6-month secondary major amputation rate. (3) Results: BME was present in 17 (22%) cases, while 59 (78%) patients were non-BME. The BME group showed a significantly higher incidence of major amputation (p < 0.001) and a significantly higher number of patients with advanced clinical stages of PAD compared to the non-BME group (p = 0.024). (4) Conclusions: Lower limb DE-CTA with VNCa application is a useful tool in the detection of BME in diabetic patients with PAD, simultaneously enabling the evaluation of the severity and location of the arterial disease for revascularization planning. BME presence could be a marker of clinically severe PAD and a possible risk factor for revascularization failure.

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

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

Abstract 12762: Plasma Lipidomic Signature of Peripheral Artery Disease in Young and Middle-Aged American Indian Individuals: The Strong Heart Family Study

Introduction: Dyslipidemia is an independent risk factor for peripheral artery disease (PAD). Ankle-brachial index (ABI) is a sensitive and cost-effective tool for screening and predicting PAD. The association between individual lipid species and the progression in subclinical PAD, assessed by change in ABI, remains to be determined, especially in understudied populations at high risk. Hypothesis: To identify individual molecular lipid species associated with PAD progression in American Indians, independent of traditional risk factors. Methods: Using an untargeted lipidomic method by liquid chromatography-mass spectrometry, we repeatedly measured 1,542 individual lipid species in 2,830 fasting plasma samples at two time points (2001-2003 and 2006-2009, mean 5 years apart) from 1,415 unique American Indians in the Strong Heart Family Study. Participants were free of prevalent PAD at both time points. ABI was measured in the right arm and bilateral (both left and right posterior tibial artery) using a handheld Doppler and was analyzed as a continuous variable. We first identified baseline lipid species associated with change in ABI by generalized estimating equation models, adjusting for baseline age, sex, BMI, smoking, eGFR, diabetes, hypertension, lipid-lowering medication and baseline ABI. We then examined the longitudinal association between change in lipid species and change in ABI, adjusting for same covariates plus baseline lipids. Results: Participants (63% female) were aged between 18-65 (mean 38) at baseline and 22-72 (mean 43) at follow-up. Higher baseline levels of 36 lipid species were positively (ORs: 1.01 - 3.60), whereas 16 lipid species were inversely (ORs: 0.26 - 0.98), associated with change in ABI. Longitudinal changes in 77 lipid species, largely glycerolipids, glycerophospholipids, and sphingolipids, were significantly associated with change in ABI during 5-year follow-up. Conclusions: Baseline plasma lipid species and their longitudinal changes over time are significantly associated with PAD progression beyond known risk factors. These findings shed light on the role of dyslipidemia in PAD among young and middle-aged American Indians who suffer high rates of obesity, diabetes and other cardiometabolic disorders.

Abstract 18998: Deletion of the Duffy Antigen Receptor for Chemokines Impairs Blood Flow Recovery in the Mouse Hindlimb Ischemia Model: Role of CCL11

Introduction: Peripheral Artery Disease (PAD) is characterized by obstruction of the arteries in the lower extremities. Impaired angiogenesis plays a major role in the progression of PAD. Pro-angiogenic and anti-angiogenic chemokines are modulated by binding to the Duffy antigen receptor for chemokines (DARC), a non-signaling receptor expressed primarily on erythrocytes. Incidence and severity of PAD is greater in Blacks, ~70% of whom do not express DARC on their erythrocytes due to a common gene variant. Here, we tested the hypothesis that hematopoietic-specific deletion of DARC impairs blood flow recovery in mouse hindlimb ischemia model. Methods: Twelve week old female DARC Flox/Vav1-Cre+ (DARC HKO ) and littermate Vav1-Cre- (wild type, WT) mice underwent unilateral femoral artery ligation and excision. Ischemic muscle tissue and plasma were analyzed at early ischemic phase (day three post ligation) and late ischemic phase (day fourteen post ligation). Blood flow recovery was measured weekly via laser Doppler imaging. Results: DARC HKO mice had poor blood flow recovery compared to WT mice (p&lt;0.05), along with reduced capillary formation and increased inflammation, necrosis and fibrosis in the ischemic gastrocnemius muscles. Amongst the various DARC-bound chemokines assayed, levels of CCL11 (a pro-angiogenic strong DARC-bound chemokine) were significantly reduced in the plasma of DARC HKO mice, both at early and late ischemic phases (p&lt;0.01). CCL11 levels strongly correlated with capillary formation in ischemic hindlimb. CCL11 levels in ischemic muscle tissue were significantly reduced in the DARC HKO mice in the early, but not late, ischemic phase. Conclusions: Loss of DARC on hematopoietic cells has a negative impact on the recovery of perfusion and angiogenesis in the murine hindlimb ischemia model, possibly due to reduced levels of CCL11 consequent to DARC deletion. These findings may be relevant to ethnic differences in susceptibility to PAD and suggest that therapies directed towards increasing CCL11 may be beneficial in Blacks with PAD.

Poor Life Prognosis of Patients with Rapid Progression of Peripheral Artery Disease

Poor Life Prognosis of Patients with Rapid Progression of Peripheral Artery Disease

Circulating Soluble EPCR Levels Are Reduced in Patients with Ischemic Peripheral Artery Disease and Associated with Markers of Endothelial and Vascular Function.

(1) Background: Endothelial dysfunction initiates cardiovascular pathologies, including peripheral artery disease (PAD). The pathophysiology of impaired new vessel formation in the presence of angiogenic stimuli, such as ischemia and inflammation, is unknown. We have recently shown in mice that reduced endothelial protein C receptor (EPCR) expression results in defective angiogenesis following experimental hindlimb ischemia. (2) Purpose: To determine soluble (s)EPCR levels in the plasma of patients with PAD and to compare them with the protein C activity and biomarkers of endothelial function, inflammation, and angiogenesis. (3) Methods and Results: Clinical tests of vascular function and immunoassays of plasma from patients with PAD stage II were compared to age- and sex-matched individuals with and without cardiovascular risk factors or PAD stage III/IV patients. sEPCR levels were significantly lower in PAD stage II patients compared to subjects with risk factors, but no PAD, and further decreased in PAD stage III/IV patients. Plasma protein C activity or levels of ADAM17, a mediator of EPCR shedding, did not differ. Significant associations between sEPCR and the ankle-brachial index (p = 0.0359), age (p = 0.0488), body mass index (p = 0.0110), and plasma sE-selectin levels (p = 0.0327) were observed. High-sensitive CRP levels and white blood cell counts were significantly elevated in PAD patients and associated with serum glucose levels, but not sEPCR. In contrast, plasma TNFα or IL1β levels did not differ. Circulating levels of VEGF were significantly elevated in PAD stage II patients (p = 0.0198), but not associated with molecular (sE-selectin) or functional (ankle-brachial index) markers of vascular health. (4) Conclusions: Our findings suggest that circulating sEPCR levels may be useful as biomarkers of endothelial dysfunction, including angiogenesis, in persons older than 35 years and that progressive loss of endothelial protein C receptors might be involved in the development and progression of PAD.

Unveiling the Genetic Footprint: Exploring Somatic Mutations in Peripheral Arterial Disease Progression.

Peripheral arterial diseases (PADs) are complex cardiovascular conditions influenced by environmental factors and somatic mutations in multiple genes involved in hematopoiesis and inflammation. While traditional risk factors, such as smoking, hypercholesterolemia, and hypertension, have been extensively studied, the role of somatic mutations in PAD progression remains underexplored. The present article intends to provide a comprehensive commentary of the molecular mechanisms, genetic landscape, prognostic significance, and clinical implications of somatic mutations in PADs. The expansion of clonal hematopoiesis of indeterminate potential (CHIP) clones in the circulating blood, named clonal hematopoiesis (CH), leads to the infiltration of these clones into atherosclerotic plaques and the production of inflammatory cytokines, increasing the risk of cardiovascular diseases, including PADs. Furthermore, recent experimental evidence has demonstrated the involvement of somatically mutated TP53 genes with a high variant allele frequency (VAF) in PAD development and prognosis. This review delves into the relationship between CH and PADs, elucidating the prevalence, impact, and underlying mechanisms of this association. This understanding paves the way for novel therapeutic approaches targeting CHIP to promote tissue regeneration and improve outcomes in PAD patients. It emphasizes the need for further research to fully unravel the genetic footprint of the disease and highlights potential clinical implications. The findings presented in this article lay the foundation for personalized medicine approaches and open avenues for the development of targeted therapies based on somatic mutation profiling.

Contrast-free ultrasound imaging for blood flow assessment of the lower limb in patients with peripheral arterial disease: a feasibility study

While being a relatively prevalent condition particularly among aging patients, peripheral arterial disease (PAD) of lower extremities commonly goes undetected or misdiagnosed due to its symptoms being nonspecific. Additionally, progression of PAD in the absence of timely intervention can lead to dire consequences. Therefore, development of non-invasive and affordable diagnostic approaches can be highly beneficial in detection and treatment planning for PAD patients. In this study, we present a contrast-free ultrasound-based quantitative blood flow imaging technique for PAD diagnosis. The method involves monitoring the variations of blood flow in the calf muscle in response to thigh-pressure-cuff-induced occlusion. Four quantitative metrics are introduced for analysis of these variations. These metrics include post-occlusion to baseline flow intensity variation (PBFIV), total response region (TRR), Lag0 response region (L0RR), and Lag4 (and more) response region (L4 + RR). We examine the feasibility of this method through an in vivo study consisting of 14 PAD patients with abnormal ankle-brachial index (ABI) and 8 healthy volunteers. Ultrasound data acquired from 13 legs in the patient group and 13 legs in the healthy group are analyzed. Out of the four utilized metrics, three exhibited significantly different distributions between the two groups (p-value < 0.05). More specifically, p-values of 0.0015 for PBFIV, 0.0183 for TRR, and 0.0048 for L0RR were obtained. The results of this feasibility study indicate the diagnostic potential of the proposed method for the detection of PAD.

Unmasking Arterial-resident Autoreactive B cells involved in Atherosclerosis and Peripheral Artery Disease Progression

Abstract Atherosclerosis activates the immune system, including B cells which secrete antibodies that bind antigens released by necrotic cells within plaques and may promote inflammation. To identify these antibodies, we isolated activated B cells from atherosclerotic ApoE-deficient mice aortas and human tibial arteries with peripheral artery disease post-amputation. Single-cell sequencing of the B cell receptors identified 35 mouse and 48 human overrepresented disease-relevant heavy and light chain pairings, which were sequentially expressed as antibody. Epitope determination was performed by human proteome array, and 14 mouse and 21 human protein targets were found with significant affinity and specificity. Mouse antigens were scrutinized by immunohistochemistry to confirm presence in inflamed plaques, and expression of these proteins were used to interrogate autoreactive antibody titers in diseased sera by ELISA. ApoE-deficient mice were immunized with the 6 most promising antigens. Serum antibody measurement showed strong, rapid, and early onset of antigen-specific antibody responses in the immunized mice compared to an adjuvant only control group. Strikingly, we saw decreased plaque accumulation in the immunized animals, suggesting antigen responses may clear pathogenic antigens before disease develops. Likewise, human antigen ELISAs comparing antigen-specific serum antibody titers to patient Framingham score for cardiovascular risk supported a role for two antigens in disease. To confirm these antigens as potential biomarkers, we will characterize the emergence of their antibody counterparts using a historical library of serum samples from individuals enrolled in the Baltimore Longitudinal Study on Aging. This work is directly funded by the National Institutes of Health – National Institute on Aging’s Intramural Research Program in the Lab of Molecular Biology and Immunology

Skeletal Muscle Bioenergetics in Critical Limb Ischemia and Diabetes

IntroductionMitochondrial dysfunction is implicated in the metabolic myopathy accompanying peripheral artery disease (PAD) and critical limb ischemia (CLI). Type-2 diabetes mellitus (T2DM) is a major risk factor for PAD development and progression to CLI and may also independently be related to mitochondrial dysfunction. We set out to determine the effect of T2DM in the relationship between CLI and muscle mitochondrial respiratory capacity and coupling control. MethodsWe studied CLI patients undergoing revascularization procedures or amputation, and non-CLI patients with or without T2DM of similar age. Mitochondrial respiratory capacity and function were determined in lower limb permeabilized myofibers by high-resolution respirometry. ResultsFourteen CLI patients (65 ± 10y) were stratified into CLI patients with (n = 8) or without (n = 6) T2DM and were compared to non-CLI patients with (n = 18; 69 ± 5y) or without (n = 19; 71 ± 6y) T2DM. Presence of CLI but not T2DM had a marked impact on all mitochondrial respiratory states in skeletal muscle, adjusted for the effects of sex. Leak respiration (State 2, P < 0.025 and State 4o, P < 0.01), phosphorylating respiration (P < 0.001), and maximal respiration in the uncoupled state (P < 0.001), were all suppressed in CLI patients, independent of T2DM. T2DM had no significant effect on mitochondrial respiratory capacity and function in adults without CLI. ConclusionsSkeletal muscle mitochondrial respiratory capacity was blunted by ∼35% in patients with CLI. T2DM was not associated with muscle oxidative capacity and did not moderate the relationship between muscle mitochondrial respiratory capacity and CLI.

Lower-limb peripheral arterial disease and amputations in people with diabetes: Risk factors, prognostic value and management

Lower-limb peripheral arterial disease (PAD), is a common manifestation of systemic atherosclerosis, resulting from a partial or complete obstruction of at least one lower-limb arteries. PAD is a major endemic disease with an excess risk of major cardiovascular events and death. It also leads to disability, high rates of lower-limb adverse events and non-traumatic amputation. In patients with diabetes, PAD is particularly frequent and has a worse prognosis than in patients without diabetes. The risk factors of PAD are comparable to those for cardiovascular disease. The ankle-brachial index is usually recommended to screen PAD despite its limited performance in patients with diabetes, affected by the presence of peripheral neuropathy, medial arterial calcification, incompressible arteries and infection. Toe brachial index and toe pressure emerge as alternative screening tools. The management of PAD requires strict control of cardiovascular risk factors including diabetes, hypertension and dyslipidaemia, the use of antiplatelet agents and lifestyle management, to reduce cardiovascular adverse events, but few randomized controlled trials have evaluated the benefits of these treatments in PAD. Several advances have been achieved in endovascular and surgical revascularization procedures, with obvious improvement in PAD prognosis. Further studies are required to increase our understanding of the pathophysiology of PAD and to evaluate the interest of different therapeutic strategies in the occurrence and progression of PAD in patients with diabetes. Here, we present a narrative and contemporary review to synthesize the key epidemiology findings, screening and diagnosis methods, and major therapeutic advances regarding PAD in patients with diabetes.

A biomechanical perspective on walking in patients with peripheral artery disease.

The most common symptom of peripheral artery disease (PAD) is intermittent claudication, which consists of debilitating leg pain during walking. In clinical settings, the presence of PAD is often noninvasively evaluated using the ankle-brachial index and imaging of the arterial supply. Furthermore, various questionnaires and functional tests are commonly used to measure the severity and negative effect of PAD on quality of life. However, these evaluations only provide information on vascular insufficiency and severity of the disease, but not regarding the complex mechanisms underlying walking impairments in patients with PAD. Biomechanical analyses using motion capture and ground reaction force measurements can provide insight into the underlying mechanisms to walking impairments in PAD. This review analyzes the application of biomechanics tools to identify gait impairments and their clinical implications on rehabilitation of patients with PAD. A total of 18 published journal articles focused on gait biomechanics in patients with PAD were studied. This narriative review shows that the gait of patients with PAD is impaired from the first steps that a patient takes and deteriorates further after the onset of claudication leg pain. These results point toward impaired muscle function across the ankle, knee, and hip joints during walking. Gait analysis helps understand the mechanisms operating in PAD and could also facilitate earlier diagnosis, better treatment, and slower progression of PAD.

A review of the current state in neointimal hyperplasia development following endovascular intervention and minor emphasis on new horizons in immunotherapy.

Endovascular strategies play a vital role in the treatment of peripheral arterial disease (PAD). However, luminal loss or restenosis after endovascular intervention remains a significant challenge. The main underlying mechanisms are negative vascular remodeling and elastic recoil in balloon angioplasty. During stenting, the main reason for this complex is neointimal proliferation. Endothelial cell injury due to endovascular intervention initiates a series of molecular events, such as overexpression of growth factors, cytokine secretion, and adhesion molecules. These induce platelet activation and inflammatory processes, which trigger the proliferation and migration of vascular smooth muscle cells into the intima, resulting in neointimal hyperplasia. During this process, PAD progression is mainly caused by chronic inflammation, in which macrophages play a central role. Of the current strategies, drug release interventions aim to suppress restenosis using antiproliferative drugs, such as sirolimus and paclitaxel, during drug release. These drugs inhibit vascular reendothelialization and reduce late in-stent restenosis. For this reason, immunotherapy can be considered an important alternative. Interventions that polarize macrophages to the M2 subtype are particularly important, as they shape the immune response in an anti-inflammatory direction and contribute to tissue repair. However, there are several challenges to overcome, such as localizing antiproliferative or polarizing agents only to areas of vascular injury. This review discusses, based on the early study observations, immunotherapeutic approaches to prevent restenosis after endovascular intervention for the treatment of PAD.

Dysregulated Genes, MicroRNAs, Biological Pathways, and Gastrocnemius Muscle Fiber Types Associated With Progression of Peripheral Artery Disease: A Preliminary Analysis.

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.

Inflammatory and Prothrombotic Biomarkers, DNA Polymorphisms, MicroRNAs and Personalized Medicine for Patients with Peripheral Arterial Disease.

Classical risk factors play a major role in the initiation and development of atherosclerosis. However, the estimation of risk for cardiovascular events based only on risk factors is often insufficient. Efforts have been made to identify biomarkers that indicate ongoing atherosclerosis. Among important circulating biomarkers associated with peripheral arterial disease (PAD) are inflammatory markers which are determined by the expression of different genes and epigenetic processes. Among these proinflammatory molecules, interleukin-6, C-reactive protein, several adhesion molecules, CD40 ligand, osteoprotegerin and others are associated with the presence and progression of PAD. Additionally, several circulating prothrombotic markers have a predictive value in PAD. Genetic polymorphisms significantly, albeit moderately, affect risk factors for PAD via altered lipoprotein metabolism, diabetes, arterial hypertension, smoking, inflammation and thrombosis. However, most of the risk variants for PAD are located in noncoding regions of the genome and their influence on gene expression remains to be explored. MicroRNAs (miRNAs) are single-stranded, noncoding RNAs that modulate gene expression at the post-transcriptional level. Patterns of miRNA expression, to some extent, vary in different atherosclerotic cardiovascular diseases. miRNAs appear to be useful in the detection of PAD and the prediction of progression and revascularization outcomes. In conclusion, taking into account one’s predisposition to PAD, i.e., DNA polymorphisms and miRNAs, together with circulating inflammatory and coagulation markers, holds promise for more accurate prediction models and personalized therapeutic options.

IgG Glycosylation Profiling of Peripheral Artery Diseases with Lectin Microarray.

Background: Inflammation plays a key role in the progression of atherosclerotic plaque for peripheral artery disease (PAD). Immunoglobulin G (IgG) glycosylation could modulate immunological effector functions and has been explored as biomarkers for various diseases. Methods: Lectin microarray was applied to analyze the expression profile of serum IgG glycosylation in patients with lower-extremity peripheral artery disease (LEPAD), carotid artery stenosis (CAS), abdominal aortic aneurysm (AAA), and healthy controls. Lectin blot was performed to validate the differences. Results: SNA (Sambucus nigra agglutinin) binding (preferred sialic acid) was significantly higher in the LEPAD (3.21 ± 2.06) and AAA (3.34 ± 2.42) groups compared to the CAS (2.47 ± 1.45) group. Significantly higher binding levels of ConA (Concanavalin A) (preferred mannose) and PSA (Pisum sativum agglutinin) (preferred fucose) were also observed in LEPAD compared to CAS patients. Among LEPAD patients, a significant lower binding level of Black bean crude (preferred GalNAc) was present for dyslipidemia patients. A higher binding level of MNA-M (Morniga M agglutinin) (preferred Mannose) and Jacalin-AIA (Artocarpus integrifolia agglutinin) (preferred Galβ3GalNAc) was observed for Fontaine severe patients. Higher binding levels of PHA-E (Phaseolus vulgaris Erythroagglutinin) and PHA-L (Phaseolus vulgaris Leucoagglutinin) (preferred Galβ4GlcNAc) were observed for diabetic patients, and higher binding of ASA (Allium sativum agglutinin) (preferred Mannose) was present in patients with hypertension. The level of high-sensitivity C-reactive protein (hsCRP) was positively associated with LTL (Lotus tetragonolobus lectin) (r = 0.44), PSA (r = 0.44), LCA (Lens Culinaris agglutinin) (r = 0.39), SNA (r = 0.57), and CSA (Cytisus sscoparius agglutinin) (r = 0.56). For CAS, symptomatic patients had lower binding levels of AAL (Aleuria aurantia lectin) (preferred fucose) and IAA (Iberis amara agglutinin) (preferred GalNAc). Blood total cholesterol level was positively associated with SNA-I (r = 0.36) and SBA (Soybean agglutinin) (r = r = 0.35). Creatinine levels were positively associated with lectins including, but not limited to, MNA-M (r = 0.42), CSA (r = 0.45), GHA (Glechoma hederacea agglutinin) (r = 0.42), and MNA-G (Morniga G agglutinin) (r = 0.45). Conclusion: LEPAD patients had increased IgG binding levels of SNA and ConA compared to CAS, which could provide potential diagnostic value. Fontaine severity was associated with Mannose-rich IgG N-glycan, while diabetic LEPAD correlated with bisecting GlcNAc. The levels of hsCRP and creatinine were positively associated with IgG fucosylation and galactosylation. Changes in IgG glycosylation may play important roles in PAD pathogenesis and progression.

Dietary Risk Factors and Eating Behaviors in Peripheral Arterial Disease (PAD).

Dietary risk factors play a fundamental role in the prevention and progression of atherosclerosis and PAD (Peripheral Arterial Disease). The impact of nutrition, however, defined as the process of taking in food and using it for growth, metabolism and repair, remains undefined with regard to PAD. This article describes the interplay between nutrition and the development/progression of PAD. We reviewed 688 articles, including key articles, narrative and systematic reviews, meta-analyses and clinical studies. We analyzed the interaction between nutrition and PAD predictors, and subsequently created four descriptive tables to summarize the relationship between PAD, dietary risk factors and outcomes. We comprehensively reviewed the role of well-studied diets (Mediterranean, vegetarian/vegan, low-carbohydrate ketogenic and intermittent fasting diet) and prevalent eating behaviors (emotional and binge eating, night eating and sleeping disorders, anorexia, bulimia, skipping meals, home cooking and fast/ultra-processed food consumption) on the traditional risk factors of PAD. Moreover, we analyzed the interplay between PAD and nutritional status, nutrients, dietary patterns and eating habits. Dietary patterns and eating disorders affect the development and progression of PAD, as well as its disabling complications including major adverse cardiovascular events (MACE) and major adverse limb events (MALE). Nutrition and dietary risk factor modification are important targets to reduce the risk of PAD as well as the subsequent development of MACE and MALE.

Differences in Comorbidities Explain Black-White Disparities in Outcomes After Femoropopliteal Endovascular Intervention.

Black adults have a higher incidence of peripheral artery disease and limb amputations than White adults in the United States. Given that peripheral endovascular intervention (PVI) is now the primary revascularization strategy for peripheral artery disease, it is important to understand whether racial differences exist in PVI incidence and outcomes. Data from fee-for-service Medicare beneficiaries ≥66 years of age from 2016 to 2018 were evaluated to determine age- and sex-standardized population-level incidences of femoropopliteal PVI among Black and White adults over the 3-year study period. Patients' first inpatient or outpatient PVIs were identified through claims codes. Age- and sex-standardized risks of the composite outcome of death and major amputation within 1 year of PVI were examined by race. Black adults underwent 928 PVIs per 100 000 Black beneficiaries compared with 530 PVIs per 100 000 White beneficiaries (risk ratio, 1.75 [95% CI, 1.73-1.77]; P<0.01). Black adults who underwent PVI were younger (mean age, 74.5 years versus 76.4 years; P<0.01), were more likely to be female (52.8% versus 42.7%; P<0.01), and had a higher burden of diabetes (70.6% versus 56.0%; P<0.01), chronic kidney disease (67.5% versus 56.6%; P<0.01), and heart failure (47.4% versus 41.7%; P<0.01) than White adults. When analyzed by indication for revascularization, Black adults were more likely to undergo PVI for chronic limb-threatening ischemia than White adults (13 023 per 21 352 [61.0%] versus 59 956 per 120 049 [49.9%]; P<0.01). There was a strong association between Black race and the composite outcome at 1 year (odds ratio, 1.21 [95% CI, 1.16-1.25]). This association persisted after adjustment for socioeconomic status (odds ratio, 1.08 [95% CI, 1.03-1.13]) but was eliminated after adjustment for comorbidities (odds ratio, 0.96 [95% CI, 0.92-1.01]). Among fee-for-service Medicare beneficiaries, Black adults had substantially higher population-level PVI incidence and were significantly more likely to experience adverse events after PVI than White adults. The association between Black race and adverse outcomes appears to be driven by a higher burden of comorbidities. This analysis emphasizes the critical need for early identification and aggressive management of peripheral artery disease risk factors and comorbidities to reduce Black-White disparities in the development and progression of peripheral artery disease and the risk of adverse events after PVI.