2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS Guideline for the Management of Lower Extremity Peripheral Artery Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

AIM: The "2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS Guideline for the Management of Lower Extremity Peripheral Artery Disease" provides recommendations to guide clinicians in the treatment of patients with lower extremity peripheral artery disease across its multiple clinical presentation subsets (ie, asymptomatic, chronic symptomatic, chronic limb-threatening ischemia, and acute limb ischemia). METHODS: A comprehensive literature search was conducted from October 2020 to June 2022, encompassing studies, reviews, and other evidence conducted on human subjects that was published in English from PubMed, EMBASE, the Cochrane Library, CINHL Complete, and other selected databases relevant to this guideline. Additional relevant studies, published through May 2023 during the peer review process, were also considered by the writing committee and added to the evidence tables where appropriate. STRUCTURE: Recommendations from the "2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease" have been updated with new evidence to guide clinicians. In addition, new recommendations addressing comprehensive care for patients with peripheral artery disease have been developed.

Activation of the Aryl Hydrocarbon Receptor in Muscle Exacerbates Ischemic Pathology in Chronic Kidney Disease.

BACKGROUND: Chronic kidney disease (CKD) accelerates the development of atherosclerosis, decreases muscle function, and increases the risk of amputation or death in patients with peripheral artery disease (PAD). However, the mechanisms underlying this pathobiology are ill-defined. Recent work has indicated that tryptophan-derived uremic solutes, which are ligands for AHR (aryl hydrocarbon receptor), are associated with limb amputation in PAD. Herein, we examined the role of AHR activation in the myopathy of PAD and CKD. METHODS: AHR-related gene expression was evaluated in skeletal muscle obtained from mice and human PAD patients with and without CKD. AHRmKO (skeletal muscle-specific AHR knockout) mice with and without CKD were subjected to femoral artery ligation, and a battery of assessments were performed to evaluate vascular, muscle, and mitochondrial health. Single-nuclei RNA sequencing was performed to explore intercellular communication. Expression of the constitutively active AHR was used to isolate the role of AHR in mice without CKD. RESULTS: PAD patients and mice with CKD displayed significantly higher mRNA expression of classical AHR-dependent genes (Cyp1a1, Cyp1b1, and Aldh3a1) when compared with either muscle from the PAD condition with normal renal function (P<0.05 for all 3 genes) or nonischemic controls. AHRmKO significantly improved limb perfusion recovery and arteriogenesis, preserved vasculogenic paracrine signaling from myofibers, increased muscle mass and strength, as well as enhanced mitochondrial function in an experimental model of PAD/CKD. Moreover, viral-mediated skeletal muscle-specific expression of a constitutively active AHR in mice with normal kidney function exacerbated the ischemic myopathy evidenced by smaller muscle masses, reduced contractile function, histopathology, altered vasculogenic signaling, and lower mitochondrial respiratory function. CONCLUSIONS: These findings establish AHR activation in muscle as a pivotal regulator of the ischemic limb pathology in CKD. Further, the totality of the results provides support for testing of clinical interventions that diminish AHR signaling in these conditions.

Evaluation of Plasma Biomarkers for Causal Association With Peripheral Artery Disease.

BACKGROUND: Hundreds of biomarkers for peripheral artery disease (PAD) have been reported in the literature; however, the observational nature of these studies limits causal inference due to the potential of reverse causality and residual confounding. We sought to evaluate the potential causal impact of putative PAD biomarkers identified in human observational studies through genetic causal inference methods. METHODS: Putative circulating PAD biomarkers were identified from human observational studies through a comprehensive literature search based on terms related to PAD using PubMed, Cochrane, and Embase. Genetic instruments were generated from publicly available genome-wide association studies of circulating biomarkers. Two-sample Mendelian randomization was used to test the association of genetically determined biomarker levels with PAD using summary statistics from a genome-wide association study of 31 307 individuals with and 211 753 individuals without PAD in the Veterans Affairs Million Veteran Program and replicated in data from FinnGen comprised of 11 924 individuals with and 288 638 individuals without PAD. RESULTS: We identified 204 unique circulating biomarkers for PAD from the observational literature, of which 173 were genetically instrumented using genome-wide association study results. After accounting for multiple testing (false discovery rate, <0.05), 10 of 173 (5.8%) biomarkers had significant associations with PAD. These 10 biomarkers represented categories including plasma lipoprotein regulation, lipid homeostasis, and protein-lipid complex remodeling. Observational literature highlighted different pathways including inflammatory response, negative regulation of multicellular organismal processes, and regulation of response to external stimuli. CONCLUSIONS: Integrating human observational studies and genetic causal inference highlights several key pathways in PAD pathophysiology. This work demonstrates that a substantial portion of biomarkers identified in observational studies are not well supported by human genetic evidence and emphasizes the importance of triangulating evidence to understand PAD pathophysiology. Although the identified biomarkers offer insights into atherosclerotic development in the lower limb, their specificity to PAD compared with more widespread atherosclerosis requires further study.

Subclinical Atherosclerosis: Part 1: What Is it? Can it Be Defined at the Histological Level?

While coronary artery disease remains a major cause of death, it is preventable. Therefore, the focus needs to shift to the early detection and prevention of atherosclerosis. Asymptomatic atherosclerosis is widely termed subclinical atherosclerosis, which is an early indicator of atherosclerotic burden, and understanding this disease is important because timely intervention could prevent future cardiovascular morbidity and mortality. We histologically recognize the earliest lesion of atherosclerosis as pathological intimal thickening, which is characterized by the presence of lipid pools. The difference between clinical atherosclerosis and subclinical atherosclerosis is whether the presence of atherosclerosis results in the clinical symptoms of ischemia, such as stroke, myocardial infarction, or chronic limb-threatening ischemia. In the absence of thrombosis, there are various types of histological plaque that encompass subclinical atherosclerosis: pathological intimal thickening, fibroatheroma, thin-cap fibroatheroma, plaque rupture, healed plaque ruptures, and fibrocalcific plaque. Plaque morphology that is most frequently responsible for acute coronary thrombosis is plaque rupture. Calcification of coronary arteries is the hallmark of atherosclerosis and is a predictor of future coronary events. Atherosclerosis occurs in other vascular beds and is most frequent in arteries of the lower extremity, followed by carotid, aorta, and coronary arteries, and the mechanisms leading to clinical symptoms are unique for each location.

Arm and ankle blood pressure indices, and peripheral artery disease, and mortality: a cohort study.

BACKGROUND AND AIMS: Few studies have compared arm and ankle blood pressures (BPs) with regard to peripheral artery disease (PAD) and mortality. These relationships were assessed using data from three large prospective clinical trials. METHODS: Baseline BP indices included arm systolic BP (SBP), diastolic BP (DBP), pulse pressure (arm SBP minus DBP), ankle SBP, ankle-brachial index (ABI, ankle SBP divided by arm SBP), and ankle-pulse pressure difference (APPD, ankle SBP minus arm pulse pressure). These measurements were categorized into four groups using quartiles. The outcomes were PAD (the first occurrence of either peripheral revascularization or lower-limb amputation for vascular disease), the composite of PAD or death, and all-cause death. RESULTS: Among 40 747 participants without baseline PAD (age 65.6 years, men 68.3%, diabetes 50.2%) from 53 countries, 1071 (2.6%) developed PAD, and 4955 (12.2%) died during 5 years of follow-up. Incident PAD progressively rose with higher arm BP indices and fell with ankle BP indices. The strongest relationships were noted for ankle BP indices. Compared with people whose ankle BP indices were in the highest fourth, adjusted hazard ratios (95% confidence interval) for each lower fourth were 1.64 (1.31-2.04), 2.59 (2.10-3.20), and 4.23 (3.44-5.21) for ankle SBP; 1.19 (0.95-1.50), 1.66 (1.34-2.05), and 3.34 (2.75-4.06) for ABI; and 1.41 (1.11-1.78), 2.04 (1.64-2.54), and 3.63 (2.96-4.45) for APPD. Similar patterns were observed for mortality. Ankle BP indices provided the highest c-statistics and classification indices in predicting future PAD beyond established risk factors. CONCLUSIONS: Ankle BP indices including the ankle SBP and the APPD best predicted PAD and mortality.

Cocoa flavanols, Nrf2 activation, and oxidative stress in peripheral artery disease: mechanistic findings in muscle based on outcomes from a randomized trial.

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.

Associations between lipoprotein(a), oxidized phospholipids, and extracoronary vascular disease.

The roles of lipoprotein(a) [Lp(a)] and related oxidized phospholipids (OxPLs) in the development and progression of coronary disease is known, but their influence on extracoronary vascular disease is not well-established. We sought to evaluate associations between Lp(a), OxPL apolipoprotein B (OxPL-apoB), and apolipoprotein(a) (OxPL-apo(a)) with angiographic extracoronary vascular disease and incident major adverse limb events (MALEs). Four hundred forty-six participants who underwent coronary and/or peripheral angiography were followed up for a median of 3.7 years. Lp(a) and OxPLs were measured before angiography. Elevated Lp(a) was defined as ≥150 nmol/L. Elevated OxPL-apoB and OxPL-apo(a) were defined as greater than or equal to the 75th percentile (OxPL-apoB ≥8.2 nmol/L and OxPL-apo(a) ≥35.8 nmol/L, respectively). Elevated Lp(a) had a stronger association with the presence of extracoronary vascular disease compared to OxPLs and was minimally improved with the addition of OxPLs in multivariable models. Compared to participants with normal Lp(a) and OxPL concentrations, participants with elevated Lp(a) levels were twice as likely to experience a MALE (odds ratio: 2.14, 95% confidence interval: 1.03, 4.44), and the strength of the association as well as the C statistic of 0.82 was largely unchanged with the addition of OxPL-apoB and OxPL-apo(a). Elevated Lp(a) and OxPLs are risk factors for progression and complications of extracoronary vascular disease. However, the addition of OxPLs to Lp(a) does not provide additional information about risk of extracoronary vascular disease. Therefore, Lp(a) alone captures the risk profile of Lp(a), OxPL-apoB, and OxPL-apo(a) in the development and progression of atherosclerotic plaque in peripheral arteries.

Association Between Mental Health Burden, Clinical Presentation, and Outcomes in Individuals With Symptomatic Peripheral Artery Disease: A Scientific Statement From the American Heart Association.

Along with the rising burden of peripheral artery disease (PAD), mental health concerns are increasingly being recognized as a comorbidity to address in the chronic disease management of symptomatic PAD. Apart from a high prevalence of comorbid mental health conditions, the role of pain and changing health behaviors and the broader impacts of illness and adaptation to living with PAD require specialized behavioral health expertise. This scientific statement builds a case that this expertise should be integrated within the multidisciplinary PAD team. Furthermore, areas such as cognitive dysfunction and palliative care are highlighted as needing psychological interventions. Although much of the evidence of the efficacy of psychological and psychotropic interventions has been extrapolated from other cardiovascular populations, evidence for the role of psychological interventions for behavior change, for example, uptake of exercise regimens, is increasingly being accrued within PAD. Areas for behavioral health needs and interactions with PAD treatment are discussed, including the use of opioids, depression management, anxiety and stress reduction interventions, the use of benzodiazepines and antidepressants, smoking cessation, rehabilitation trajectories after amputation, and the role of cognitive decline for PAD treatment and outcomes. A case summary highlights the stigma around mental health and vascular disease and the fragmentation of care. This scientific statement provides remarks for building a road map for integrated behavioral PAD care and potential solutions to overcome these barriers. Instrumental to reaching these changes are interprofessional advocacy efforts and initiatives that help break down the stigma around mental health and promote evidence-based collaborative, nonhierarchical, and multidisciplinary PAD care.

Deletion of the aryl hydrocarbon receptor in endothelial cells improves ischemic angiogenesis in chronic kidney disease.

Chronic kidney disease (CKD) is a strong risk factor for peripheral artery disease (PAD) that is associated with worsened clinical outcomes. CKD leads to the accumulation of tryptophan metabolites that are associated with adverse limb events in PAD and are ligands of the aryl hydrocarbon receptor (AHR), which may regulate ischemic angiogenesis. To test if endothelial cell-specific deletion of the AHR (AHRecKO) alters ischemic angiogenesis and limb function in mice with CKD subjected to femoral artery ligation. Male AHRecKO mice with CKD displayed better limb perfusion recovery and enhanced ischemic angiogenesis compared with wild-type mice with CKD. However, the improved limb perfusion did not result in better muscle performance. In contrast to male mice, deletion of the AHR in female mice with CKD had no impact on perfusion recovery or angiogenesis. With the use of primary endothelial cells from male and female mice, treatment with indoxyl sulfate uncovered sex-dependent differences in AHR activating potential and RNA sequencing revealed wide-ranging sex differences in angiogenic signaling pathways. Endothelium-specific deletion of the AHR improved ischemic angiogenesis in male, but not female, mice with CKD. There are sex-dependent differences in Ahr activating potential within endothelial cells that are independent of sex hormones.NEW & NOTEWORTHY This study provides novel insights into the mechanisms by which chronic kidney disease worsens ischemic limb outcomes in an experimental model of peripheral artery disease. Deletion of the aryl hydrocarbon receptor (AHR) in the endothelium improved ischemic angiogenesis suggesting that AHR inhibition could be a viable therapeutic target; however, this effect was only observed in male mice. Subsequent analysis in primary endothelial cells reveals sex differences in Ahr activating potential independent of sex hormones.

Clinical physiology: the crucial role of MRI in evaluation of peripheral artery disease.

Peripheral artery disease (PAD) is a common vascular disease that primarily affects the lower limbs and is defined by the constriction or blockage of peripheral arteries and may involve microvascular dysfunction and tissue injury. Patients with diabetes have more prominent disease of microcirculation and develop peripheral neuropathy, autonomic dysfunction, and medial vascular calcification. Early and accurate diagnosis of PAD and disease characterization are essential for personalized management and therapy planning. Magnetic resonance imaging (MRI) provides excellent soft tissue contrast and multiplanar imaging capabilities and is useful as a noninvasive imaging tool in the comprehensive physiological assessment of PAD. This review provides an overview of the current state of the art of MRI in the evaluation and characterization of PAD, including an analysis of the many applicable MR imaging techniques, describing the advantages and disadvantages of each approach. We also present recent developments, future clinical applications, and future MRI directions in assessing PAD. The development of new MR imaging technologies and applications in preclinical models with translation to clinical research holds considerable potential for improving the understanding of the pathophysiology of PAD and clinical applications for improving diagnostic precision, risk stratification, and treatment outcomes in patients with PAD.

Effects of acute hyperoxia on autonomic function and coronary tone in patients with peripheral artery disease.

Numerous studies have shown that oxidative stress plays an important role in peripheral artery disease (PAD). Prior reports suggested autonomic dysfunction in PAD. We hypothesized that responses of the autonomic nervous system and coronary tone would be impaired in patients with PAD during exposure to acute hyperoxia, an oxidative stressor. In 20 patients with PAD and 16 healthy, sex- and age-matched controls, beat-by-beat heart rate (HR, from ECG) and blood pressure (BP, with Finometer) were recorded for 10 min during room air breathing and 5 min of hyperoxia. Cardiovagal baroreflex sensitivity and HR variability (HRV) were evaluated as measures of autonomic function. Transthoracic coronary echocardiography was used to assess peak coronary blood flow velocity (CBV) in the left anterior descending coronary artery. Cardiovagal baroreflex sensitivity at rest was lower in PAD than in healthy controls. Hyperoxia raised BP solely in the patients with PAD, with no change observed in healthy controls. Hyperoxia induced an increase in cardiac parasympathetic activity assessed by the high-frequency component of HRV in healthy controls but not in PAD. Indices of parasympathetic activity were lower in PAD than in healthy controls throughout the trial as well as during hyperoxia. Hyperoxia induced coronary vasoconstriction in both groups, while the coronary perfusion time fraction was lower in PAD than in healthy controls. These results suggest that the response in parasympathetic activity to hyperoxia (i.e., oxidative stress) is blunted and the coronary perfusion time is shorter in patients with PAD.NEW & NOTEWORTHY Patients with peripheral artery disease (PAD) showed consistently lower parasympathetic activity and blunted cardiovagal baroreflex sensitivity compared with healthy individuals. Notably, hyperoxia, which normally boosts parasympathetic activity in healthy individuals, failed to induce this response in patients with PAD. These data suggest altered autonomic responses during hyperoxia in PAD.

Comparative analysis of atherosclerotic cardiovascular disease burden between ages 20-54 and over 55 years: insights from the Global Burden of Disease Study 2019.

BACKGROUND: To systematically analyze differences in atherosclerotic cardiovascular disease (ASCVD) burden between young and older adults. METHODS: We estimated the prevalence, mortality, and disability-adjusted life years (DALYs) of ASCVD, including ischemic heart disease (IHD), ischemic stroke (IS), and peripheral artery disease (PAD), in individuals aged 20-54 and > 55 years from 1990-2019, utilizing data from the 2019 Global Burden of Disease Study. The annual percentage changes (EAPCs) for age-specific prevalence, mortality, or DALY rates were calculated to quantify the temporal trends of ASCVD burden. We also analyzed population attribution fractions (PAF) of premature ASCVD mortality and DALYs for different risk factors and compared the burden of extremely premature, premature, and non-premature ASCVD cases based on clinical classifications. RESULTS: From 1990-2019, the global prevalence rates of IHD, IS, and PAD in the 20-54 years age group increased by 20.55% (from 694.74 to 837.49 per 100,000 population), 11.50% (from 439.48 to 490.03 per 100,000 population), and 7.38% (from 384.24 to 412.59 per 100,000 population), respectively. Conversely, the ASCVD prevalence in > 55years age group decreased. Adverse outcome burdens, including mortality and DALYs, varied among ASCVD subtypes. The decrease in the mortality/DALY burden of IHD and IS was lower in the 20-54 years group than in the > 55 years group. For PAD, DALYs among those aged 20-54 increased but decreased among those aged > 55 years. When grouped according to socio-demographic index (SDI) values, lower SDI regions exhibited a higher proportion of young ASCVD burden. The prevalence of young IHD, IS, and PAD in low SDI regions reached 20.70%, 40.05%, and 19.31% in 2019, respectively, compared with 12.14%, 16.32%, and 9.54%, respectively, in high SDI regions. Metabolic risks were the primary contributors to the ASCVD burden in both age groups. Increased susceptibility to ambient particulate matter pollution and inadequate control of high body-mass index and high fasting plasma glucose in young individuals may partially explain the differing temporal trends between young and older individuals. CONCLUSIONS: The ASCVD burden in young individuals may become a growing global health concern, especially in areas with lower socioeconomic development levels that require more effective primary prevention strategies.

Sex differences in the purinergic 2 receptor-mediated blood pressure response to treadmill exercise in rats with simulated peripheral artery disease.

We investigated the role played by ATP-sensitive purinergic 2 (P2) receptors in evoking the pressor response to treadmill exercise in male and female rats with and without femoral arteries that were ligated for ∼72 h to induce simulated peripheral artery disease (PAD). We hypothesized that PPADS (P2 receptor antagonist, 10 mg iv) would reduce the pressor response to 4 min of treadmill exercise (15 m·min-1, 1° incline) and steady-state exercise plasma norepinephrine (NE) values in male and female rats, and that the magnitude of effect of PPADS would be greater in rats with simulated PAD ("ligated") than in sham-operated rats. In males, PPADS significantly reduced the difference between steady-state exercise and baseline mean arterial pressure (ΔMAP) response to treadmill exercise in sham (n = 8; pre-PPADS: 12 ± 2, post-PPADS: 1 ± 5 mmHg; P = 0.037) and ligated (n = 4; pre-PPADS: 20 ± 2, post-PPADS: 11 ± 3 mmHg; P = 0.028) rats with a similar magnitude of effect observed between groups (P = 0.720). In females, PPADS had no effect on the ΔMAP response to treadmill exercise in sham (n = 6; pre-PPADS: 9 ± 2, post-PPADS: 7 ± 2 mmHg; P = 0.448) or ligated (n = 6; pre-PPADS: 15 ± 2, post-PPADS: 16 ± 3 mmHg; P = 0.684) rats. When NE values were grouped by sex independent of ligation/sham status, PPADS significantly reduced plasma NE in male (P = 0.016) and female (P = 0.027) rats. The data indicate that P2 receptors contribute to the sympathetic response to exercise in both male and female rats but that the sympathoexcitatory role for P2 receptors translates into an obligatory role in the blood pressure response to exercise in male but not in female rats.NEW & NOTEWORTHY Here, we demonstrate that purinergic 2 (P2) receptors contribute significantly to the blood pressure response to treadmill exercise in male rats both with and without simulated PAD induced by femoral artery ligation. We found no role for P2 receptors in the blood pressure response to treadmill exercise in female rats, thus revealing clear sex differences in P2 receptor-mediated blood pressure control during exercise.

Lessons from PROMINENT and prospects for pemafibrate.

The neutral result of the PROMINENT trial has led to questions about the future for pemafibrate. This commentary discusses possible reasons for the lack of benefit observed in the trial. There were, however, indicators suggesting therapeutic potential in microvascular ischaemic complications associated with peripheral artery disease, with subsequent analysis showing reduction in the incidence of lower extremity ischaemic ulceration or gangrene. Reassurance about the safety of pemafibrate, together with emerging data from PROMINENT and experimental studies, also suggest benefit with pemafibrate in non-alcoholic fatty liver disease (alternatively referred to as metabolic dysfunction-associated steatotic liver disease) and microangiopathy associated with diabetes, which merit further study.

Challenges and opportunities in the management of type 2 diabetes in patients with lower extremity peripheral artery disease: a tailored diagnosis and treatment review.

Lower extremity peripheral artery disease (PAD) often results from atherosclerosis, and is highly prevalent in patients with type 2 diabetes mellitus (T2DM). Individuals with T2DM exhibit a more severe manifestation and a more distal distribution of PAD compared to those without diabetes, adding complexity to the therapeutic management of PAD in this particular patient population. Indeed, the management of PAD in patients with T2DM requires a multidisciplinary and individualized approach that addresses both the systemic effects of diabetes and the specific vascular complications of PAD. Hence, cardiovascular prevention is of the utmost importance in patients with T2DM and PAD, and encompasses smoking cessation, a healthy diet, structured exercise, careful foot monitoring, and adherence to routine preventive treatments such as statins, antiplatelet agents, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. It is also recommended to incorporate glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) in the medical management of patients with T2DM and PAD, due to their demonstrated cardiovascular benefits. However, the specific impact of these novel glucose-lowering agents for individuals with PAD remains obscured within the background of cardiovascular outcome trials (CVOTs). In this review article, we distil evidence, through a comprehensive literature search of CVOTs and clinical guidelines, to offer key directions for the optimal medical management of individuals with T2DM and lower extremity PAD in the era of GLP-1RA and SGLT2i.

Risk factors for and risk of all-cause and atherosclerotic cardiovascular disease mortality in people with type 2 diabetes and peripheral artery disease: an observational, register-based cohort study.

BACKGROUND: Type 2 diabetes (T2D) and peripheral artery disease (PAD) are recognized as independent risk factors contributing to excess mortality. Contemporary observational studies exploring the associations of risk factors, and risk of all-cause and atherosclerotic cardiovascular disease mortality in persons with T2D following the onset of incident peripheral artery disease are limited. The objectives of this study were to investigate the associations of risk factors, and assess mortality risks in people with T2D compared with controls without T2D after the onset of PAD. METHODS: All persons with T2D (n = 150,215) registered in the Swedish National Diabetes Register between 2005 and 2009 were included, along with 346,423 controls without T2D matched for sex and age. Data were retrieved from several national registries, capturing information on risk factors, onset of incident peripheral artery disease, other comorbidities, socioeconomic factors, and outcomes. To compare persons with T2D and controls following the onset of peripheral artery disease regarding the risk of all-cause, and atherosclerotic cardiovascular disease mortality, Cox proportional hazard models and Kaplan-Meier curves were employed. A gradient-boosting model was utilized to estimate the relative statistical contribution of risk factors to the modeling of incident mortality risk in people with both T2D and peripheral artery disease. RESULTS: Crude rates of incident all-cause mortality were higher in individuals with T2D compared with controls, following the onset of PAD (600.4 (95% CI, 581.4-619.8) per 10,000 person-years versus 549.1 (95% CI, 532.1-566.5) per 10,000 person-years). Persons with T2D had an adjusted hazard ratio (HR) for all-cause mortality of 1.12 (95% CI, 1.05-1.19, P < 0.01) compared with controls after onset of incident PAD. The comparable adjusted HR for cardiovascular mortality was 1.13 (95% CI, 1.07-1.19, P < 0.01). High age and hyperglycemia at baseline played a significant role in contributing to the predictive models for incident all-cause and cardiovascular mortality among individuals with both T2D and PAD. CONCLUSIONS: The presence of T2D with concomitant PAD is related to an increased risk of both all-cause and cardiovascular mortality compared with individuals with only PAD. This argues for implementing optimized and intensive treatment strategies for individuals with both conditions.

Using machine learning to predict outcomes following suprainguinal bypass.

OBJECTIVE: Suprainguinal bypass for peripheral artery disease (PAD) carries important surgical risks; however, outcome prediction tools remain limited. We developed machine learning (ML) algorithms that predict outcomes following suprainguinal bypass. METHODS: The Vascular Quality Initiative database was used to identify patients who underwent suprainguinal bypass for PAD between 2003 and 2023. We identified 100 potential predictor variables from the index hospitalization (68 preoperative [demographic/clinical], 13 intraoperative [procedural], and 19 postoperative [in-hospital course/complications]). The primary outcomes were major adverse limb events (MALE; composite of untreated loss of patency, thrombectomy/thrombolysis, surgical revision, or major amputation) or death at 1 year following suprainguinal bypass. Our data were split into training (70%) and test (30%) sets. Using 10-fold cross-validation, we trained six ML models using preoperative features (Extreme Gradient Boosting [XGBoost], random forest, Naïve Bayes classifier, support vector machine, artificial neural network, and logistic regression). The primary model evaluation metric was area under the receiver operating characteristic curve (AUROC). The best performing algorithm was further trained using intra- and postoperative data. Model robustness was evaluated using calibration plots and Brier scores. Performance was assessed on subgroups based on age, sex, race, ethnicity, rurality, median Area Deprivation Index, symptom status, procedure type, prior intervention for PAD, concurrent interventions, and urgency. RESULTS: Overall, 16,832 patients underwent suprainguinal bypass, and 3136 (18.6%) developed 1-year MALE or death. Patients with 1-year MALE or death were older (mean age, 64.9 vs 63.5 years; P < .001) with more comorbidities, had poorer functional status (65.7% vs 80.9% independent at baseline; P < .001), and were more likely to have chronic limb-threatening ischemia (67.4% vs 47.6%; P < .001) than those without an outcome. Despite being at higher cardiovascular risk, they were less likely to receive acetylsalicylic acid or statins preoperatively and at discharge. Our best performing prediction model at the preoperative stage was XGBoost, achieving an AUROC of 0.92 (95% confidence interval [CI], 0.91-0.93). In comparison, logistic regression had an AUROC of 0.67 (95% CI, 0.65-0.69). Our XGBoost model maintained excellent performance at the intra- and postoperative stages, with AUROCs of 0.93 (95% CI, 0.92-0.94) and 0.98 (95% CI, 0.97-0.99), respectively. Calibration plots showed good agreement between predicted and observed event probabilities with Brier scores of 0.12 (preoperative), 0.11 (intraoperative), and 0.10 (postoperative). Of the top 10 predictors, nine were preoperative features including chronic limb-threatening ischemia, previous procedures, comorbidities, and functional status. Model performance remained robust on all subgroup analyses. CONCLUSIONS: We developed ML models that accurately predict outcomes following suprainguinal bypass, performing better than logistic regression. Our algorithms have potential for important utility in guiding perioperative risk mitigation strategies to prevent adverse outcomes following suprainguinal bypass.

Socioeconomic factors predict successful supervised exercise therapy completion.

OBJECTIVE: Supervised exercise therapy (SET) for patients with intermittent claudication (IC) can lower the risk of progression to chronic limb-threatening ischemia and amputation, while preserving and restoring functional status. Despite supporting evidence, it remains underutilized, and among those who initiate programs, attrition rates are extremely high. We hypothesize that socioeconomic factors may represent significant barriers to SET completion. METHODS: Patients with IC referred to SET at a multi-hospital, single-institution health care system (2018-2022) from a prospectively maintained database were retrospectively analyzed. Our primary endpoint was SET program completion and graduation, defined as completion of 36 sessions. Our secondary endpoints were vascular intervention within 1 year of referral and change in ankle-brachial index (ABI). Baseline demographics were assessed using standard statistical methods. Predictors of SET graduation were analyzed using multivariable logistic regression generating adjusted odds ratios (aORs) with 95% confidence intervals (CIs). Change in ABI was analyzed using t-test between subgroups. Reasons for attrition were tabulated. Patient Health Questionnaire-9 (PHQ-9), metabolic equivalent level, Vascular QOL, Duke Activity Status, and ABI were analyzed using paired t-tests across the entire cohort. RESULTS: Fifty-two patients met inclusion criteria: mean age 67.85 ± 10.69 years, 19 females (36.54%), mean baseline ABI of 0.77 ± 0.16. The co-pays for 100% of patients were fully covered by primary and secondary insurance plans. Twenty-one patients (40.38%) completed SET. On multivariable analysis, residence in a ZIP code with median household income <$47,000 (aOR, 0.10; 95% CI, 0.01-0.76; P = .03) and higher body mass index (aOR, 0.81; 95% CI, 0.67-0.99; P = .04) were significant barriers to SET graduation. There were no differences in ABI change or vascular intervention within 1 year between graduates and non-graduates. Non-graduates reported transportation challenges (25.00%), lack of motivation (20.83%), and illness/functional limitation (20.83%) as primary reasons for SET attrition. Metabolic Equivalent Level (P ≤ .01) and Duke Activity Status scores (P = .04) were significantly greater after participating in a SET program. CONCLUSIONS: Although SET participation improves lower extremity and functionality outcomes, only 40% of referred patients completed therapy in our cohort. Our findings suggest that both socioeconomic and functional factors influence the odds of completing SET programs, indicating a need for holistic pre-referral assessment to facilitate enhanced program accessibility for these populations.

Development and evaluation of a prediction model for peripheral artery disease-related major adverse limb events using novel biomarker data.

OBJECTIVE: Prognostic tools for individuals with peripheral artery disease (PAD) remain limited. We developed prediction models for 3-year PAD-related major adverse limb events (MALE) using demographic, clinical, and biomarker data previously validated by our group. METHODS: We performed a prognostic study using a prospectively recruited cohort of patients with PAD (n = 569). Demographic/clinical data were recorded including sex, age, comorbidities, previous procedures, and medications. Plasma concentrations of three biomarkers (N-terminal pro-B-type natriuretic peptide [NT-proBNP], fatty acid binding protein 3 [FABP3], and FABP4) were measured at baseline. The cohort was followed for 3 years. MALE was the primary outcome (composite of open/endovascular vascular intervention or major amputation). We trained three machine learning models with 10-fold cross-validation using demographic, clinical, and biomarker data (random forest, decision trees, and Extreme Gradient Boosting [XGBoost]) to predict 3-year MALE in patients. Area under the receiver operating characteristic curve (AUROC) was the primary model evaluation metric. RESULTS: Three-year MALE was observed in 162 patients (29%). XGBoost was the top-performing predictive model for 3-year MALE, achieving the following performance metrics: AUROC = 0.88 (95% confidence interval [CI], 0.84-0.94); sensitivity, 88%; specificity, 84%; positive predictive value, 83%; and negative predictive value, 91% on test set data. On an independent validation cohort of patients with PAD, XGBoost attained an AUROC of 0.87 (95% CI, 0.82-0.90). The 10 most important predictors of 3-year MALE consisted of: (1) FABP3; (2) FABP4; (3) age; (4) NT-proBNP; (5) active smoking; (6) diabetes; (7) hypertension; (8) dyslipidemia; (9) coronary artery disease; and (10) sex. CONCLUSIONS: We built robust machine learning algorithms that accurately predict 3-year MALE in patients with PAD using demographic, clinical, and novel biomarker data. Our algorithms can support risk stratification of patients with PAD for additional vascular evaluation and early aggressive medical management, thereby improving outcomes. Further validation of our models for clinical implementation is warranted.

Outcomes of endovascular intervention for atherosclerotic lesions confined to the popliteal artery.

OBJECTIVE: Most surgeons employ an endovascular-first approach to the treatment of peripheral arterial disease (PAD), but controversy remains regarding the ideal interventions for the management of isolated popliteal artery disease (IPAD). Indeed, there are a paucity of data that compare outcomes of popliteal stents vs other peripheral vascular interventions (PVIs). The goal of this study was to evaluate outcomes of PVIs in IPAD. METHODS: The Vascular Study Group of New England database was queried for all IPAD PVIs performed for atherosclerotic occlusive disease from 2010 to 2021. Those with at least 1 year of follow-up data available were included for analysis. The primary endpoint was 1-year freedom from a composite target lesion (TL) treatment failure that included restenosis >50% on duplex, reintervention, or ipsilateral major amputation. RESULTS: We included 689 procedures performed on 634 patients. Of these, 250 (36.3%) were treated with plain balloons (POBA), 215 (31.2%) had stents, 170 (24.7%) had special balloons (drug-coated, cutting, or lithotripsy), and 54 (7.8%) atherectomies were performed. Stent placement was associated with lower freedom from TL treatment failure (72.6%) than special balloon (81.2%; P = .048) and atherectomy (88.9%; P = .012), but not POBA (76.8%; P = .293). On multivariable logistic regression, stents (odds ratio, 0.637; P = .021) and preoperative P2Y12 inhibitor therapy (odds ratio, 0.683; P = .048) were both associated with lower freedom from intervention failure. CONCLUSIONS: Popliteal stent placement is associated with a higher rate of TL treatment failure at 1 year when compared with other PVIs including special balloon angioplasty and atherectomy, but not POBA, and should therefore be avoided in favor of special balloons or atherectomy whenever feasible.