Peripheral Arterial Disease

Peripheral artery disease (PAD) results from atherosclerosis and chronic narrowing of lower limb arteries, leading to decreased muscle perfusion. Current treatments are suboptimal, partly due to limited understanding of PAD muscle pathology. Here we used single-cell RNA sequencing and spatial transcriptomics to analyze the composition of the muscle microenvironment in non-ischemic patients and patients with PAD. We identified ATF3/ATF4+ endothelial cells (ECs) that exhibit altered angiogenic and immune regulatory profiles during PAD and confirmed that ATF4 signaling in ECs is required for effective ischemia recovery. In addition, capillary ECs display features of endothelial-to-mesenchymal transition. Furthermore, LYVE1hiMHCIIlow macrophages are the dominant macrophage population in human muscle, adopting a more pro-inflammatory profile during PAD. Finally, we analyzed alterations in intercellular communication within the muscle microenvironment during PAD and confirmed that EC-derived factors can influence macrophage polarization. This dataset deeply characterizes the PAD muscle microenvironment and provides a resource for exploration of targeted therapies.

Peripheral artery disease (PAD) with hyperlipidemia adds significantly to the national burden of cardiovascular disease. However, population-level trends in mortality for these conditions are not well understood. We used nationally representative data to investigate long-term temporal patterns and disparities in PAD and hyperlipidemia related mortality in the United States. This descriptive analysis analyzed death records from the CDC WONDER database from 1999 to 2024. The age-adjusted mortality rates (AAMRs) per 100,000 people were calculated for each demographic and geographic strata. AAMRs were standardized to 2000 U.S. standard population. Temporal trends in AAMRs were analyzed using Joinpoint regression to estimate the average annual percent change (AAPC) with 95% confidence intervals (CIs) and p value. Between 1999 and 2024, a total of 148,416 PAD with hyperlipidemia-related deaths were recorded among U.S. adults ≥ 25 years. The national AAMR rose from 0.74 in 1999 to 3.92 in 2024, corresponding to an overall AAPC of 6.32. Both sexes experienced increasing mortality, though men had higher rates and faster growth compared with women. By race/ethnicity, AAMRs increased across all groups, with the steepest relative rise among Hispanic individuals, followed by Non-Hispanic (NH) Black, NH White, and NH Asian or Pacific Islander populations. Geographic disparities were observed, with state-level AAMRs ranging from 0.92 in Georgia to 5.06 in Vermont, and the highest regional mean AAMR in the West (2.93). Finally, rural areas consistently exhibited higher mean AAMRs than urban areas, with slightly steeper increase over time. AAMRs related to PAD and hyperlipidemia have increased more than fivefold, with disproportionately higher rates among men, Hispanic populations, residents of Western regions, and those in rural areas. These patterns suggest widening disparities in vascular health and underscore the need for strengthened preventive efforts, improved lipid management, and more equitable access to cardiovascular care.

Diabetes mellitus (DM) is a chronic non-communicable disease associated with macroangiopathy and microangiopathy, with disabling or even life-threatening complications. In the present study, we aimed to analyze the association between insulin resistance (IR) and inflammation biomarkers and peripheral arterial disease (PAD) and diabetic peripheral neuropathy (DPN), respectively. The study had a cross-sectional design and evaluated a panel of IR related indices and inflammatory biomarkers commonly used in clinical and epidemiological research, including the triglyceride-glucose (TyG) index and its obesity related derivates, cholesterol, HDL, glucose (CHG) index, lipid-derived ratios, and composite inflammatory indices, together with interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα) and C-reactive protein (CRP) in 110 subjects, according to the presence or absence of PAD and DPN, respectively. In the PAD (+) group, TyG-waist-to-height-ratio (TyG-WHtR) and CHG recorded significantly increased values (p = 0.042, respectively p p = 0.007). In addition, in the PAD (+) subjects, IL-6 and systemic immune inflammation index (SII) recorded significantly increased values (p = 0.026, respectively, p = 0.015) and TNFα, monocyte to lymphocyte ratio (MLR) and C-reactive protein to albumin ratio (CAR) recorded significantly increased values in DPN (+) subjects (p = 0.028, respectively, p = 0.008, and p = 0.038). We developed a score with a good discriminatory performance for PAD and DPN, including DM duration, TyG-WHtR, SII, MLR and CAR (AUROC 0.822 in PAD, respectively 0.848 in DPN, p < 0.001). A composite score combining IR and inflammatory biomarkers showed strong discriminatory performance for lower limb complications in type 2 diabetes, suggesting a valuable tool for early detection and prevention.

IntroductionThromboelastography (TEG) is a point-of-care test that provides a quantitative of measure of the dynamic changes in clot strength and viscoelastic properties of a whole blood sample. Although conventional coagulation tests are well established in vascular surgery, they do not identify the hypercoagulable state and response to antiplatelet therapy. The role of TEG in peripheral arterial disease (PAD) is unclear and its application as demonstrated in the literature has undergone limited appraisal. The objectives of our study were to identify whether TEG can inform individualised thromboprophylaxis and predict thrombotic events following re-vascularisation in PAD.MethodsWe adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and a PRISMA checklist was completed. PubMed and Embase databases were searched from inception until October 2024 using the relevant Medical Subject Headings terms. Only full-text articles published in the English language reporting the outcomes in PAD with TEG or TEG with platelet mapping (TEG-PM) were analysed. The protocol was registered on the PROSPERO database (ID:CRD42024580627).FindingsThe analysis included 14 studies. TEG-PM was able to quantify the response to antiplatelet therapy and potentially guide individualised thromboprophylaxis. The parameters maximum amplitude, platelet aggregation and platelet inhibition were able to predict thrombotic events. However, substantial heterogeneity in thromboprophylaxis, surgical procedures and comorbidities was observed in the studies.ConclusionsTEG-PM could serve as a valuable tool for tailoring antiplatelet therapy and predicting outcomes in patients with PAD. Further studies including randomised controlled trials are needed to validate the findings.