The bodyweight walking distance product and its relationship with clinical markers in patients with symptomatic peripheral artery disease.

PURPOSE: The six-minute walk test (6MWT) is extensively employed to evaluate gait impairment in patients with symptomatic peripheral artery disease (PAD) and has been associated with different health outcomes. However, various approaches exist for calculating and interpreting the six-minute test in order to address the needs of patients more effectively. Therefore, we investigated how these different approaches correlate with functional capacity and cardiovascular health in patients with symptomatic PAD. METHODS: In total, 227 PAD patients [65.2% men and 67 (13) y.o.] were included in this cross-sectional study. The 6MWT was performed along a 30-meter corridor and the distance was expressed in three ways: absolute (described as the meters walked during the test), relativized (based on the results of the 6MWT in healthy individuals), and DW (multiplying the body weight in kilograms by the absolute distance in the 6MWT). A functional capacity z-score was calculated using the results of the handgrip strength test, 4-meter walking test, and sit-and-stand test. A cardiovascular parameter z-score was calculated with data on brachial and central blood pressure, the low-frequency component/high-frequency component ratio, and carotid-femoral pulse wave velocity. RESULTS: The absolute (b = 0.30, 95%CI: 18-0.43, R² = 0.11, p < 0.001) and DW (b = 0.40, 95%CI: 27-0.53, R² = 0.17, p < 0.001) measures were related to functional capacity, independently of sex, age, and the ankle-arm index of the patients. Neither absolute nor DW were related to cardiovascular health. The relativized measure was not associated with either functional capacity or cardiovascular health. CONCLUSION: In patients with symptomatic PAD, absolute and DW measures are related to functional capacity, but not cardiovascular function.

Undiagnosed and Untreated Peripheral Complications of Diabetes: Findings from a Pilot Study on Diabetes-Related Foot Diseases (DFD) in Patients with Glycemic Disorders.

BACKGROUND Diabetes-related foot disease (DFD) is a serious complication of diabetes, increasing the risk of amputation. Coimplications are preventable, but most diabetics do not receive proper screening and treatment, despite indications. This study was a pilot screening of diabetes-related foot disease in a group of people with glycemic disorders. MATERIAL AND METHODS We recruited 143 volunteers over 40 years of age. In the final analysis, we included 85 people diagnosed with glycemic disorders (diabetes or prediabetes), for whom we performed a total of 170 foot measurements. We screened for peripheral artery disease using: foot pulse, ankle-brachial index (manual and automatic), toe-brachial index, and transcutaneous oxygen pressure (TcPO2). To screen for diabetic peripheral neuropathy, we used indicators of loss of protective sensation: pressure perception and temperature perception, and plantar pressure distribution. RESULTS A history of diabetes was reported by 26 (30.6%) of the subjects. Disorders of at least 1 foot occurred in 20 (66.7%) subjects with diagnosed diabetes and in 10 (17%) subjects declaring no diabetes. Higher risk and DFD category were correlated with duration of diabetes (r=0.68, p=0.007), glycemic levels (r=0.56, p=0.001), age (r=0.57, p=0.007), and the presence of other diabetes complications. The best predictor of risk in DFD was manual ABI, p=0.001; followed by automatic ABI, p=0.006. CONCLUSIONS Our results showed that peripheral complications of diabetes, such as DFD, often remain undiagnosed and untreated despite the high risk of developing ulcers. There is a need for multi-center screening studies.

Skeletal muscle desmin alterations following revascularization in peripheral artery disease claudicants.

Peripheral artery disease (PAD) is characterized by varying severity of arterial stenosis, exercise induced claudication, malperfused tissue precluding normal healing and skeletal muscle dysfunction. Revascularization interventions improve circulation, but post-reperfusion changes within the skeletal muscle are not well characterized. This study investigates if revascularization enhanced hemodynamics increases walking performance with concurrent improvement of mitochondrial function and reverses abnormal skeletal muscle morphological features that develop with PAD. Fifty-eight patients completed walking performance testing and muscle biopsy before and 6 months after revascularization procedures. Muscle fiber morphology, desmin structure, and mitochondria respiration assessments before and after the revascularization were evaluated. Revascularization improved limb hemodynamics, walking function, and muscle morphology. Qualitatively not all participants recovered normal structural architecture of desmin in the myopathic myofibers after revascularization. Heterogenous responses in the recovery of desmin structure following revascularization may be caused by other underlying factors not reversed with hemodynamic improvements. Revascularization interventions clinically improve patient walking ability and can reverse the multiple subcellular functional and structural abnormalities in muscle cells. Further study is needed to characterize desmin structural remodeling with improvements in skeletal muscle morphology and function.

Feasibility of performing treadmill walking test for patients with peripheral arterial occlusive disease by the advanced practice nurses.

AIM: The treadmill walking test with post-exercise pressure measurement can be used as a diagnostic test and could classify peripheral arterial disease of the lower limbs. It can also exclude the diagnosis allowing to raise the possibility of differential diagnoses. In this study, we assessed the feasibility of performing treadmill test by advanced practice nurse to assess suspected lower extremity peripheral artery disease patients. DESIGN AND METHOD: This is a longitudinal monocentric study to assess the feasibility of a treadmill walking test performed by an advanced practice nurse. The primary endpoint was the number of tests performed during this period. The secondary objectives were to evaluate the reasons for requesting the test, the main results obtained in terms of the test's contribution and diagnoses, and patients' clinical characteristics. RESULTS: From February to May 2023, amongst 31 patients who underwent the treadmill walking test, 4 tests were able to rule out peripheral arterial disease and to detect differential diagnoses. For the remaining 27 patients, 4 had stage IIa of the Leriche classification, 23 had stage IIb, 2 of which were associated with a narrow lumbar spine. In contrast to the usual report, the APN's report on the walking test included an identification of cardiovascular risk factors, as well as a possible medical reorientation linked to the correction of a detected cardiovascular risk factor. CONCLUSION: The treadmill walking test can be performed by an advanced practice nurse. He/She added a comprehensive/global patient management, with the detection of cardiovascular risk factors. This new profession led to an increase in the number of tests performed of more than 50% over the period and reduced the time to access the test.

Predictors of bleeding complications during catHeter-dirEcted thrombolysis for peripheral arterial occlusions (POCHET).

INTRODUCTION: The risk of major bleeding complications in catheter directed thrombolysis (CDT) for acute limb ischemia (ALI) remains high, with reported major bleeding complication rates in up to 1 in every 10 treated patients. Fibrinogen was the only predictive marker used for bleeding complications in CDT, despite the lack of high quality evidence to support this. Therefore, recent international guidelines recommend against the use of fibrinogen during CDT. However, no alternative biomarkers exist to effectively predict CDT-related bleeding complications. The aim of the POCHET biobank is to prospectively assess the rate and etiology of bleeding complications during CDT and to provide a biobank of blood samples to investigate potential novel biomarkers to predict bleeding complications during CDT. METHODS: The POCHET biobank is a multicentre prospective biobank. After informed consent, all consecutive patients with lower extremity ALI eligible for CDT are included. All patients are treated according to a predefined standard operating procedure which is aligned in all participating centres. Baseline and follow-up data are collected. Prior to CDT and subsequently every six hours, venous blood samples are obtained and stored in the biobank for future analyses. The primary outcome is the occurrence of non-access related major bleeding complications, which is assessed by an independent adjudication committee. Secondary outcomes are non-major bleeding complications and other CDT related complications. Proposed biomarkers to be investigated include fibrinogen, to end the debate on its usefulness, anti-plasmin and D-Dimer. DISCUSSION AND CONCLUSION: The POCHET biobank provides contemporary data and outcomes of patients during CDT for ALI, coupled with their blood samples taken prior and during CDT. Thereby, the POCHET biobank is a real world monitor on biomarkers during CDT, supporting a broad spectrum of future research for the identification of patients at high risk for bleeding complications during CDT and to identify new biomarkers to enhance safety in CDT treatment.

Randomized Trial Comparing a Stent-Avoiding With a Stent-Preferred Strategy in Complex Femoropopliteal Lesions.

BACKGROUND: Limited comparative data exist on different interventional strategies for endovascular revascularization of complex femoropopliteal interventions. OBJECTIVES: In this study, the authors aimed to compare a stent-avoiding (SA) vs a stent-preferred (SP) strategy, promoting optimal lesion preparation and the use of drug-eluting technologies in both arms. METHODS: Within a prospective, multicenter, pilot study, 120 patients with symptomatic complex femoropopliteal lesions (Rutherford classification 2-4, mean lesion length 187.7 ± 78.3 mm, 79.2% total occlusions) were randomly assigned in a 1:1 fashion to endovascular treatment with either paclitaxel-coated balloons or polymer-coated, paclitaxel-eluting stents. Lesion preparation including the use of devices for plaque modification and/or removal was at the operators' discretion in both treatment arms. RESULTS: In the SA group, lesion preparation was more frequently performed (71.7% SA [43/60] vs 51.7% [31/60] SP; P = 0.038) with a high provisional stenting rate (48.3% [29/60]). At the 12-month follow-up, primary patency was 78.2% (43/55) in the SA group and 78.6% (44/56) in the SP group (P = 1.0; relative risk: 0.995; 95% CI: 0.818-1.210). Freedom from major adverse events was determined in 93.1% (54/58) in the SA group and in 94.9% (56/59) in the SP group (P = 0.717; relative risk: 0.981; 95% CI: 0.895-1.075), with all adverse events attributable to clinically driven target lesion revascularization. CONCLUSIONS: Both endovascular strategies promoting lesion preparation before the use of drug-eluting devices suggest promising efficacy and safety results in complex femoropopliteal procedures with a high proportion of total occlusions through 12 months. Ongoing follow-up will show whether different results emerge over time. (Best Endovascular Strategy for Complex Lesions of the Superficial Femoral Artery [BEST-SFA]; NCT03776799).

Superoxide Dismutase and Clopidogrel: A Potential Role in Peripheral Arterial Disease Treatment.

Oxidative stress plays a crucial role in the pathogenesis of peripheral artery disease (PAD). This study aimed to investigate the effect of clopidogrel on oxidative stress in PAD patients. Seventy subjects were divided into three groups: PAD patients before treatment (B-PAD), PAD patients after treatment with clopidogrel (A-PAD), and healthy controls. Serum levels of superoxide dismutase (SOD), copper (Cu), zinc (Zn), manganese (Mn), and oxidized protein were measured. SOD activities were also determined. The results showed that SOD activities, and SOD specific activities were significantly decreased in PAD patients compared to healthy individuals. After treatment with clopidogrel, SOD activities, and SOD specific activities were continuously decrease in PAD patients. The SOD and oxidized protein concentrations were significantly increased in PAD patients compared to healthy individuals. After treatment with clopidogrel, the oxidized protein concentration was significantly decreased, while SOD concentration was significantly increased in PAD patients. These findings suggest that the treatment by clopidogrel stimulated the production of the enzyme but the ratio of active enzyme remained low. The decrease in oxidized protein can be explained by the treatment having antioxidant efficacy that may have compensated for the deficiency in enzyme activity and led to a decrease in oxidized protein. Additionally, the results of this study provide promising evidence that oxidative stress biomarkers including SOD concentration, T-SOD activity, Mn-SOD activity, and oxidized protein levels have potential utility in the diagnosis and management of PAD.

Body surface area is positively associated with ankle-brachial index.

BACKGROUND: Ankle-brachial index (ABI) measurement is a widely used diagnostic test for lower extremity artery disease. Previously, a larger body surface area (BSA) has been associated with lower blood pressure and lower 2-h post-load glucose concentrations in the oral glucose tolerance test. Our aim was to evaluate whether BSA has an impact on ABI and the prevalence of lower ABI values. METHODS: ABI measurements were performed on 972 subjects aged 45 to 70 years at high cardiovascular disease (CVD) risk. Subjects with previously diagnosed kidney disease, CVD, and diabetes were excluded. Their BSA was calculated by the Mosteller formula. Study subjects were divided into five BSA levels corresponding to 12.5th, 25th, 25th, 25th, and 12.5th percentiles of the total distribution. Effect modification by BSA in ABI between sexes was derived from a four-knot restricted cubic splines regression model. RESULTS: After adjustments for age, sex, pulse pressure, glucose regulation, waist circumference, alcohol intake, smoking status, leisure-time physical activity and medication, BSA level had a positive linear relationship with ABI (p for linearity <0.001). When BSA was less than 2.0 m2, there was no difference between the sexes, but when BSA was higher than 2.0 m2, men had higher ABI. CONCLUSION: BSA shows a positive linear relationship with ABI in CVD risk subjects without manifested CVD. The difference in ABI between men and women is modified by BSA and is appreciable when BSA is larger than 2.0 m2.

Correlation and risk factors of peripheral and cervicocephalic arterial atherosclerosis in patients with ischemic cerebrovascular disease.

Patients with ischemic cerebrovascular disease (ICVD) frequently develop concomitant peripheral artery disease (PAD) or renal artery stenosis (RAS), and multiterritorial atherosclerotic patients usually have a worse prognosis. We aimed to evaluate the status of peripheral atherosclerosis (AS) and cervicocephalic AS (CAS) in ICVD patients with AS, their correlation, and related risk factors contributing to coexisting cervicocephalic-peripheral AS (CPAS). Based on the severity and extent of AS evaluated by computed tomography angiography and ultrasound, the degree of AS was triple categorized to assess the correlation between CAS and PAD/RAS. CAS and PAD/RAS were defined as the most severe stenosis being ≥ 50% luminal diameter in cervicocephalic or lower limb arteries, and a peak systolic velocity at the turbulent site being ≥ 180 cm/s in the renal artery. Among 403 patients with symptom onset within 30 days, CAS, PAD, and RAS occurrence rates were 68.7%, 25.3%, and 9.9%, respectively. PAD was independently associated with the degree of extracranial and intracranial CAS (p = 0.042, OR = 1.428, 95% CI 1.014-2.012; p = 0.002, OR = 1.680, 95% CI 1.206-2.339), while RAS was independently associated with the degree of extracranial CAS (p = 0.001, OR = 2.880, 95% CI 1.556-5.329). Independent CPAS risk factors included an ischemic stroke history (p = 0.033), increased age (p < 0.01), as well as elevated fibrinogen (p = 0.021) and D-dimer levels (p = 0.019). In conclusion, the occurrence rates of RAS and PAD in ICVD patients with AS is relatively high, and with the severity of RAS or PAD increase, the severity of CAS also increase. Strengthening the evaluation of peripheral AS and controlling elevated fibrinogen might be crucial for preventing and delaying the progression of multiterritorial AS in ICVD patients with AS, thereby improving risk stratification and promoting more effective prevention and treatment strategies.

Validation of a New Ankle Brachial Index Measurement System Using Pulse Wave Velocity.

Peripheral artery disease (PAD) is a common circulatory disorder characterized by the accumulation of fats, cholesterol, and other substances in the arteries that restrict blood flow to the extremities, especially the legs. The ankle brachial index (ABI) is a highly reliable and valid non-invasive test for diagnosing PAD. However, the traditional method has limitations. These include the time required, the need for Doppler equipment, the training of clinical staff, and patient discomfort. PWV refers to the speed at which an arterial pressure wave propagates along the arteries, and this speed is conditioned by arterial elasticity and stiffness. To address these limitations, we have developed a system that uses electrocardiogram (ECG) and photoplethysmography (PPG) signals to calculate pulse wave velocity (PWV). We propose determining the ABI based on this calculation. Validation was performed on 22 diabetic patients, and the results demonstrate the accuracy of the system, maintaining a margin of ±0.1 compared with the traditional method. This confirms the correlation between PWV and ABI and positions this technique as a promising alternative to overcome some of the limitations of the conventional method.

Long-Term Mortality Predictors Using a Machine-Learning Approach in Patients With Chronic Limb-Threatening Ischemia After Peripheral Vascular Intervention.

BACKGROUND: Patients with chronic limb-threatening ischemia (CLTI) face a high long-term mortality risk. Identifying novel mortality predictors and risk profiles would enable individual health care plan design and improved survival. We aimed to leverage a random survival forest machine-learning algorithm to identify long-term all-cause mortality predictors in patients with CLTI undergoing peripheral vascular intervention. METHODS AND RESULTS: Patients with CLTI undergoing peripheral vascular intervention from 2017 to 2018 were derived from the Medicare-linked VQI (Vascular Quality Initiative) registry. We constructed a random survival forest to rank 66 preprocedural variables according to their relative importance and mean minimal depth for 3-year all-cause mortality. A random survival forest of 2000 trees was built using a training sample (80% of the cohort). Accuracy was assessed in a testing sample (20%) using continuous ranked probability score, Harrell C-index, and out-of-bag error rate. A total of 10 114 patients were included (mean±SD age, 72.0±11.0 years; 59% men). The 3-year mortality rate was 39.1%, with a median survival of 1.4 years (interquartile range, 0.7-2.0 years). The most predictive variables were chronic kidney disease, age, congestive heart failure, dementia, arrhythmias, requiring assisted care, living at home, and body mass index. A total of 41 variables spanning all domains of the biopsychosocial model were ranked as mortality predictors. The accuracy of the model was excellent (continuous ranked probability score, 0.172; Harrell C-index, 0.70; out-of-bag error rate, 29.7%). CONCLUSIONS: Our random survival forest accurately predicts long-term CLTI mortality, which is driven by demographic, functional, behavioral, and medical comorbidities. Broadening frameworks of risk and refining health care plans to include multidimensional risk factors could improve individualized care for CLTI.

Lower extremity arterial disease vs. coronary artery disease: mortality differences after revascularization.

BACKGROUND AND AIMS: Patients undergoing revascularization for lower extremity arterial disease (LEAD) may face a higher risk of mortality than those with coronary artery disease (CAD). This study aimed to characterize the difference in mortality risk between patients undergoing revascularization for LEAD and CAD and identify associated factors. METHODS: The 1-year database of 10 754 patients undergoing revascularization for CAD (n = 6349) and LEAD (n = 4405) was analysed. Poisson regression models were used to characterize interpopulation differences in mortality, adjusting for baseline clinical features, including age, sex, polyvascular disease, comorbidities, medications, and vulnerabilities. RESULTS: Individuals with LEAD were older, were more likely to have polyvascular disease, had more comorbidities, and received fewer cardioprotective drugs than those with CAD. Vulnerabilities remained more common in the LEAD group even after adjusting for these clinical features. The crude risk ratio of mortality incidence for LEAD vs. CAD was 2.91 (95% confidence interval, 2.54-3.34), attenuated to 2.14 (1.83-2.50) after controlling for age, sex, and polyvascular disease. The percentage attenuation in the excessive mortality associated with LEAD was 29%. The stepwise addition of comorbidities, medications, and vulnerabilities as adjusting factors attenuated the incidence risk ratio to 1.48 (1.26-1.72), 1.33 (1.12-1.58), and 1.17 (0.98-1.39), respectively, and increased the percentage attenuation to 64%, 73%, and 86%, respectively. CONCLUSIONS: Mortality risk was almost three-fold higher in patients undergoing revascularization for LEAD than in those with CAD. The excessive mortality was considerably attributable to inter-group differences in baseline characteristics, including potentially clinically or socially modifiable factors.

Effects of additional exercise therapy after a successful vascular intervention for people with symptomatic peripheral arterial disease.

BACKGROUND: Peripheral arterial disease (PAD) is characterised by obstruction or narrowing of the large arteries of the lower limbs, usually caused by atheromatous plaques. Most people with PAD who experience intermittent leg pain (intermittent claudication) are typically treated with secondary prevention strategies, including medical management and exercise therapy. Lower limb revascularisation may be suitable for people with significant disability and those who do not show satisfactory improvement after conservative treatment. Some studies have suggested that lower limb revascularisation for PAD may not confer significantly more benefits than supervised exercise alone for improved physical function and quality of life. It is proposed that supervised exercise therapy as adjunctive treatment after successful lower limb revascularisation may confer additional benefits, surpassing the effects conferred by either treatment alone. OBJECTIVES: To assess the effects of a supervised exercise programme versus standard care following successful lower limb revascularisation in people with PAD. SEARCH METHODS: We searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, two other databases, and two trial registers, most recently on 14 March 2023. SELECTION CRITERIA: We included randomised controlled trials which compared supervised exercise training following lower limb revascularisation with standard care following lower limb revascularisation in adults (18 years and older) with PAD. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were maximum walking distance or time (MWD/T) on the treadmill, six-minute walk test (6MWT) total distance, and pain-free walking distance or time (PFWD/T) on the treadmill. Our secondary outcomes were changes in the ankle-branchial index, all-cause mortality, changes in health-related quality-of-life scores, reintervention rates, and changes in subjective measures of physical function. We analysed continuous data by determining the mean difference (MD) and 95% confidence interval (CI), and dichotomous data by determining the odds ratio (OR) with corresponding 95% CI. We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: We identified seven studies involving 376 participants. All studies involved participants who received either additional supervised exercise or standard care after lower limb revascularisation. The studies' exercise programmes varied, and included supervised treadmill walking, combined exercise, and circuit training. The duration of exercise therapy ranged from six weeks to six months; follow-up time ranged from six weeks to five years. Standard care also varied between studies, including no treatment or advice to stop smoking, lifestyle modifications, or best medical treatment. We classified all studies as having some risk of bias concerns. The certainty of the evidence was very low due to the risk of bias, inconsistency, and imprecision. The meta-analysis included only a subset of studies due to concerns regarding data reporting, heterogeneity, and bias in most published research. The evidence was of very low certainty for all the review outcomes. Meta-analysis comparing changes in maximum walking distance from baseline to end of follow-up showed no improvement (MD 159.47 m, 95% CI -36.43 to 355.38; I2 = 0 %; 2 studies, 89 participants). In contrast, exercise may improve the absolute maximum walking distance at the end of follow-up compared to standard care (MD 301.89 m, 95% CI 138.13 to 465.65; I2 = 0 %; 2 studies, 108 participants). Moreover, we are very uncertain if there are differences in the changes in the six-minute walk test total distance from baseline to treatment end between exercise and standard care (MD 32.6 m, 95% CI -17.7 to 82.3; 1 study, 49 participants), and in the absolute values at the end of follow-up (MD 55.6 m, 95% CI -2.6 to 113.8; 1 study, 49 participants). Regarding pain-free walking distance, we are also very uncertain if there are differences in the mean changes in PFWD from baseline to treatment end between exercise and standard care (MD 167.41 m, 95% CI -11 to 345.83; I2 = 0%; 2 studies, 87 participants). We are very uncertain if there are differences in the absolute values of ankle-brachial index at the end of follow-up between the intervention and standard care (MD 0.01, 95% CI -0.11 to 0.12; I2 = 62%; 2 studies, 110 participants), in mortality rates at the end of follow-up (OR 0.92, 95% CI 0.42 to 2.00; I2 = 0%; 6 studies, 346 participants), health-related quality of life at the end of follow-up for the physical (MD 0.73, 95% CI -5.87 to 7.33; I2 = 64%; 2 studies, 105 participants) and mental component (MD 1.04, 95% CI -6.88 to 8.95; I2 = 70%; 2 studies, 105 participants) of the 36-item Short Form Health Survey. Finally, there may be little to no difference in reintervention rates at the end of follow-up between the intervention and standard care (OR 0.91, 95% CI 0.23 to 3.65; I2 = 65%; 5 studies, 252 participants). AUTHORS' CONCLUSIONS: There is very uncertain evidence that additional exercise therapy after successful lower limb revascularisation may improve absolute maximal walking distance at the end of follow-up compared to standard care. Evidence is also very uncertain about the effects of exercise on pain-free walking distance, six-minute walk test distance, quality of life, ankle-brachial index, mortality, and reintervention rates. Although it is not possible to confirm the effectiveness of supervised exercise compared to standard care for all outcomes, studies did not report any harm to participants from this intervention after lower limb revascularisation. Overall, the evidence incorporated into this review was very uncertain, and additional evidence is needed from large, well-designed, randomised controlled studies to more conclusively demonstrate the role additional exercise therapy has after lower limb revascularisation in people 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.

Clinical use of polygenic risk scores for detection of peripheral artery disease and cardiovascular events.

We have previously shown that polygenic risk scores (PRS) can improve risk stratification of peripheral artery disease (PAD) in a large, retrospective cohort. Here, we evaluate the potential of PRS in improving the detection of PAD and prediction of major adverse cardiovascular and cerebrovascular events (MACCE) and adverse events (AE) in an institutional patient cohort. We created a cohort of 278 patients (52 cases and 226 controls) and fit a PAD-specific PRS based on the weighted sum of risk alleles. We built traditional clinical risk models and machine learning (ML) models using clinical and genetic variables to detect PAD, MACCE, and AE. The models' performances were measured using the area under the curve (AUC), net reclassification index (NRI), integrated discrimination improvement (IDI), and Brier score. We also evaluated the clinical utility of our PAD model using decision curve analysis (DCA). We found a modest, but not statistically significant improvement in the PAD detection model's performance with the inclusion of PRS from 0.902 (95% CI: 0.846-0.957) (clinical variables only) to 0.909 (95% CI: 0.856-0.961) (clinical variables with PRS). The PRS inclusion significantly improved risk re-classification of PAD with an NRI of 0.07 (95% CI: 0.002-0.137), p = 0.04. For our ML model predicting MACCE, the addition of PRS did not significantly improve the AUC, however, NRI analysis demonstrated significant improvement in risk re-classification (p = 2e-05). Decision curve analysis showed higher net benefit of our combined PRS-clinical model across all thresholds of PAD detection. Including PRS to a clinical PAD-risk model was associated with improvement in risk stratification and clinical utility, although we did not see a significant change in AUC. This result underscores the potential clinical utility of incorporating PRS data into clinical risk models for prevalent PAD and the need for use of evaluation metrics that can discern the clinical impact of using new biomarkers in smaller populations.