The Associations between Peripheral Artery Disease and Physical Outcome Measures in Men and Women with Chronic Kidney Disease.

BACKGROUND: Peripheral artery disease (PAD) is highly prevalent and associated with significant morbidity and mortality, but sex-based differences are incompletely understood. We sought to define the associations between PAD and physical outcome measures and to determine if these associations differed by sex in the Chronic Renal Insufficiency Cohort. METHODS: Among 3,543 participants, we assessed the cross-sectional relationship between PAD severity defined by ankle-brachial index; and (1) physical activity (metabolic equivalent [MET]-hr/wk), (2) walking pace (slow versus medium and/or fast), and (3) physical function (12-item Short Form Health Survey [SF-12]) at baseline. RESULTS: In a multivariable linear regression model, PAD severity was not associated with physical activity defined by total MET-hr per wk in men or women (P = 0.432). However, PAD severity was significantly associated with walking activity (P = 0.037), although this relationship did not differ by sex (P = 0.130). Similarly, PAD severity was significantly associated with walking pace (P < 0.001), although this relationship did not differ by sex (P = 0.086). In contrast, there was an independent association between PAD severity and SF-12 (P = 0.018), with a significant interaction by sex (P < 0.001). CONCLUSIONS: These data suggest that tools used to evaluate the functional consequences of PAD should focus on walking activity and walking pace, as well as physical function, where sex-specific associations should be accounted for.

Measurement of skeletal muscle perfusion dynamics with pseudo-continuous arterial spin labeling (pCASL): Assessment of relative labeling efficiency at rest and during hyperemia, and comparison to pulsed arterial spin labeling (PASL).

PURPOSE: To compare calf skeletal muscle perfusion measured with pulsed arterial spin labeling (PASL) and pseudo-continuous arterial spin labeling (pCASL) methods, and to assess the variability of pCASL labeling efficiency in the popliteal artery throughout an ischemia-reperfusion paradigm. MATERIALS AND METHODS: At 3T, relative pCASL labeling efficiency was experimentally assessed in five subjects by measuring the signal intensity of blood in the popliteal artery just distal to the labeling plane immediately following pCASL labeling or control preparation pulses, or without any preparation pulses throughout separate ischemia-reperfusion paradigms. The relative label and control efficiencies were determined during baseline, hyperemia, and recovery. In a separate cohort of 10 subjects, pCASL and PASL sequences were used to measure reactive hyperemia perfusion dynamics. RESULTS: Calculated pCASL labeling and control efficiencies did not differ significantly between baseline and hyperemia or between hyperemia and recovery periods. Relative to the average baseline, pCASL label efficiency was 2 ± 9% lower during hyperemia. Perfusion dynamics measured with pCASL and PASL did not differ significantly (P > 0.05). Average leg muscle peak perfusion was 47 ± 20 mL/min/100g or 50 ± 12 mL/min/100g, and time to peak perfusion was 25 ± 3 seconds and 25 ± 7 seconds from pCASL and PASL data, respectively. Differences of further metrics parameterizing the perfusion time course were not significant between pCASL and PASL measurements (P > 0.05). CONCLUSION: No change in pCASL labeling efficiency was detected despite the almost 10-fold increase in average blood flow velocity in the popliteal artery. pCASL and PASL provide precise and consistent measurement of skeletal muscle reactive hyperemia perfusion dynamics. J. MAGN. RESON. IMAGING 2016;44:929-939.

Rapid High-resolution, Self-registered, Dual Lumen-contrast MRI Method for Vessel-wall Assessment in Peripheral Artery Disease:: A Preliminary Investigation.

RATIONALE AND OBJECTIVES: Contrast-enhanced angiographic evaluation by magnetic resonance imaging (MRI) and computed tomography (CT) is the reference standard for assessing peripheral artery disease (PAD). However, because PAD and diabetes often coexist, the prevalence of renal insufficiency is a major challenge to contrast-based angiography. The objective of this work is to describe and demonstrate a new application of three-dimensional double-echo steady-state (3D DESS) as a noncontrast vascular MRI method for evaluating peripheral atherosclerosis at 3 Tesla (3T). MATERIALS AND METHODS: A water-selective 3D DESS pulse sequence was designed to simultaneously collect two steady-state free-precession signals (free induction decay and Echo) yielding "black blood" (BB) and "gray blood" (GB) images. For completeness Bloch equation, simulations were performed to characterize DESS signals of various tissues including blood at different velocities and to assess two healthy subjects for the purpose of pulse sequence optimization. Exploratory studies were performed as an add-on protocol to an existing study involving patients with PAD. To evaluate the method's specificity for detecting calcification, images from select patients were compared against CT angiography. RESULTS: Simulations agreed qualitatively with in vivo images supporting DESS' potential for generating distinct lumen contrast (GB vs BB). Lesions representing calcium were easily identifiable on the basis of signal void occurring on both image types and were confirmed by CT angiography. Further, BB allowed visualization of stent restenosis, and data suggest its ability to visualize acute thrombus by virtue of T2 weighting. CONCLUSION: Preliminary investigation and results suggest noncontrast 3D DESS to have the potential to improve diagnosis of PAD patients by providing detailed structural assessment of vessel-wall architecture.

Multiparametric assessment of vascular function in peripheral artery disease: dynamic measurement of skeletal muscle perfusion, blood-oxygen-level dependent signal, and venous oxygen saturation.

BACKGROUND: Endothelial dysfunction present in patients with peripheral artery disease may be better understood by measuring the temporal dynamics of blood flow and oxygen saturation during reactive hyperemia than by conventional static measurements. METHODS AND RESULTS: Perfusion, Intravascular Venous Oxygen saturation, and T2* (PIVOT), a recently developed MRI technique, was used to measure the response to an ischemia-reperfusion paradigm in 96 patients with peripheral artery disease of varying severity and 10 healthy controls. Perfusion, venous oxygen saturation SvO2, and T2* were each quantified in the calf at 2-s temporal resolution, yielding a dynamic time course for each variable. Compared with healthy controls, patients had a blunted and delayed hyperemic response. Moreover, patients with lower ankle-brachial index had (1) a more delayed reactive hyperemia response time, manifesting as an increase in time to peak perfusion in the gastrocnemius, soleus, and peroneus muscles, and in the anterior compartment, (2) an increase in the time to peak T2* measured in the soleus muscle, and (3) a prolongation of the posterior tibial vein SvO2 washout time. Intrasession and intersession repeatability were also assessed. Results indicated that time to peak perfusion and time to peak T2* were the most reliable extracted time course metrics. CONCLUSIONS: Perfusion, dynamic SvO2, and T2* response times after induced ischemia are highly correlated with peripheral artery disease severity. Combined imaging of peripheral microvascular blood flow and dynamics of oxygen saturation with Perfusion, intravascular SvO2, and T2* may be a useful tool to investigate the pathophysiology of peripheral artery disease.

Cost-effectiveness of supervised exercise, stenting, and optimal medical care for claudication: results from the Claudication: Exercise Versus Endoluminal Revascularization (CLEVER) trial.

BACKGROUND: Both supervised exercise (SE) and stenting (ST) improve functional status, symptoms, and quality of life compared with optimal medical care (OMC) in patients with claudication. The relative cost-effectiveness of these strategies is not well defined. METHODS AND RESULTS: The Claudication: Exercise Versus Endoluminal Revascularization (CLEVER) study randomized patients with claudication due to aortoiliac stenosis to a 6-month SE program, to ST, or to OMC. Participants who completed 6-month follow-up (n=98) were included in a health economic analysis through 18 months. Costs were assessed using resource-based methods and hospital billing data. Quality-adjusted life-years were estimated using the EQ-5D. Markov modeling based on the in-trial results was used to explore the impact of assumptions about the longer term durability of observed differences in quality of life. Through 18 months, mean healthcare costs were $5178, $9804, and $14 590 per patient for OMC, SE, and ST, respectively. Measured quality-adjusted life-years through 18 months were 1.04, 1.16, and 1.20. In our base case analysis, which assumed that observed differences in quality of life would dissipate after 5 years, the incremental cost-effectiveness ratios were $24 070 per quality-adjusted life-year gained for SE versus OMC, $41 376 for ST versus OMC, and $122 600 for ST versus SE. If the treatment effect of ST was assumed to be more durable than that of SE, the incremental cost-effectiveness ratio for ST versus SE became more favorable. CONCLUSIONS: Both SE and ST are economically attractive by US standards relative to OMC for the treatment of claudication in patients with aortoiliac disease. ST is more expensive than SE, with uncertain incremental benefit. CLINICAL TRIAL REGISTRATION URL: www.clinicaltrials.gov, Unique identifier: NCT00132743.

Personalized cytomic assessment of vascular health: Evaluation of the vascular health profile in diabetes mellitus.

BACKGROUND: An inexpensive and accurate blood test does not currently exist that can evaluate the cardiovascular health of a patient. This study evaluated a novel high dimensional flow cytometry approach in combination with cytometric fingerprinting (CF), to comprehensively enumerate differentially expressed subsets of pro-angiogenic circulating progenitor cells (CPCs), involved in the repair of vasculature, and microparticles (MPs), frequently involved in inflammation and thrombosis. CF enabled discovery of a unique pattern, involving both MPs and CPCs and generated a personalized signature of vascular health, the vascular health profile (VHP). METHODS: Levels of CPCs and MPs were measured with a broad panel of cell surface markers in a population with atherosclerosis and type 2 diabetes mellitus (DM) and age-similar Healthy controls (HC) using an unbiased computational approach, termed CF. RESULTS: Circulating hematopoietic stem and progenitor cell (CHSPCAng) levels were detected at significantly lower concentrations in DM (P < 0.001), whereas levels of seven phenotypically distinct MPs were present at significantly higher concentrations in DM patients and one MP subset was present at significantly lower concentration in DM patients. Collectively, the combination of CHSPC(Ang) and MP levels was more informative than any one measure alone. CONCLUSIONS: This work provides the basis for a personalized cytomic vascular health profile that may be useful for a variety of applications including drug development, clinical risk assessment and companion diagnostics.

Claudication: exercise vs endoluminal revascularization (CLEVER) study update.

The Claudication: Exercise vs Endoluminal Revascularization (CLEVER) Study is a prospective multicenter randomized clinical trial designed to compare the relative clinical and cost-effectiveness of invasive revascularization with stents to supervised exercise rehabilitation in a cohort with moderate to severe claudication due to aortoiliac insufficiency. The study is currently enrolling at twenty-eight sites in the US and Canada. Enrollment of 217 participants is planned, with data collected at baseline, six months, and 18 months. The primary study endpoint is maximum walking duration (MWD) on a graded treadmill test; secondary endpoints include community-based walking, markers of cardiovascular disease risk (body mass index, waist circumference, blood pressure, lipid profile, glucose tolerance, and plasma fibrinogen), health-related quality of life, and cost effectiveness. There are currently sixty randomized participants; recruitment is projected to end in July 2010 and final study results reported in June 2012.

Skeletal muscle microvascular flow in progressive peripheral artery disease: assessment with continuous arterial spin-labeling perfusion magnetic resonance imaging.

OBJECTIVES: We present the novel application of continuous arterial spin-labeling (CASL) magnetic resonance imaging (MRI) for the measurement of calf muscle perfusion in subjects with progressive peripheral arterial disease (PAD). BACKGROUND: Peripheral arterial disease is largely considered to be a disease of conduit vessels. The impact of PAD upon microvascular flow in the end-organ, muscle, remains unknown. Continuous arterial spin-labeling is a noninvasive MRI method capable of measuring microvascular flow and might assist in our understanding of the impact of PAD upon the microvasculature. METHODS: Forty subjects with varying degrees of PAD and 17 age-matched PAD-free subjects were recruited and underwent measurement of the ankle-to-brachial index (ABI) and CASL. Peak hyperemic flow (PHF) and time-to-peak (TTP) were computed and assessed as a function of ABI and calf muscle group. RESULTS: An ABI dependence was found in both PHF (p = 0.04) and TTP (p < 10(-4)). Whereas TTP increased almost immediately with increasing PAD severity, PHF was, in contrast, relatively well preserved until later stages of disease. CONCLUSIONS: The CASL flow measurements correlate with disease state as measured by ABI and demonstrate preserved microvascular flow reserve in the presence of early to intermediate vascular disease.

The Claudication: Exercise Vs. Endoluminal Revascularization (CLEVER) study: rationale and methods.

Intermittent claudication is the primary symptom of peripheral arterial disease, affecting between 1 and 3 million Americans. Symptomatic improvement can be achieved by endovascular revascularization, but such procedures are invasive, expensive, and may be associated with procedural adverse events. Medical treatment options, including claudication medications and supervised exercise training, are also known to be effective, albeit also with associated limitations. The CLEVER (Claudication: Exercise Vs. Endoluminal Revascularization) study, funded by the Heart, Lung, and Blood Institute of the National Institutes of Health, is a prospective, multicenter, randomized, controlled clinical trial evaluating the relative efficacy, safety, and health economic impact of four treatment strategies for people with aortoiliac peripheral arterial disease and claudication. The treatment arms are: (1) optimal medical care (claudication pharmacotherapy); (2) primary stent placement; (3) supervised exercise rehabilitation; and (4) combined stenting with supervised exercise rehabilitation. The CLEVER study is a 5-year randomized, controlled clinical trial to be conducted at approximately 25 centers in the United States that will monitor 252 patients and their responses to treatment during an 18-month follow-up period. The primary end point is change in maximum walking duration on a graded treadmill test. Secondary end points include the change at 18 months in maximum walking duration from baseline, comparisons of free-living daily activity levels assessed by pedometer, health-related quality of life, and cost-effectiveness. Other analyses include the effect of these treatment strategies on anthropomorphic and physiologic variables, including body mass index, waist circumference, blood pressure, pulse pressure, and resting pulse as well as biochemical markers of cardiovascular health, including fasting lipids, fibrinogen, C-reactive protein, and hemoglobin A 1c values.

Carotid intima-media thickness testing by non-sonographer clinicians: the office practice assessment of carotid atherosclerosis study.

BACKGROUND: The purpose of this study was to determine whether a non-sonographer clinician (NSC) could obtain ultrasound images of the carotid artery, measure carotid intima-media thickness (CIMT), and identify findings indicating increased cardiovascular risk in an office setting. METHODS: Eight NSCs from five sites were trained to use a handheld ultrasound device to screen the carotid arteries for plaques and to measure CIMT. RESULTS: NSCs scanned 150 subjects who provided 900 images, of which 873 (97%) were interpretable. Differences between NSCs and the core laboratory were small (0.002 +/- 0.004 mm) and bioequivalent (P(TOST) < 0.05) with a low coefficient of variation (3.9% +/- 0.5%). There was > or = 90% agreement on the presence of CIMT > or = 75th percentile and > or = 80% agreement on plaque presence. CONCLUSIONS: This is the first multicenter study to show that NSCs can obtain images of the carotid arteries using a handheld ultrasound device, accurately measure CIMT, and identify findings indicating increased cardiovascular risk.

Guidelines for noninvasive vascular laboratory testing: a report from the American Society of Echocardiography and the Society for Vascular Medicine and Biology.

Accompanying the rapid growth of interest in percutaneous vascular interventions, there has been increasing interest among cardiologists in performing noninvasive vascular testing using ultrasound. In an attempt to provide recommendations on the best practices in vascular laboratory testing, this report has been prepared by a writing group from the American Society of Echocardiography (ASE) and the Society for Vascular Medicine and Biology. The document summarizes principles integral to vascular duplex ultrasound--including color Doppler, spectral Doppler waveform analysis, power Doppler, and the use of contrast. Appropriate indications and interpretation of carotid artery, renal artery, abdominal aorta, and peripheral artery ultrasound imaging are described. A dedicated section summarizes noninvasive techniques for physiologic vascular testing of the lower extremity arteries--including measurement of segmental pressures and pulse volume plethysmography. The use of exercise testing in the evaluation of peripheral artery disease, ultrasound evaluation of the lower extremities after percutaneous revascularization, and the diagnosis and management of iatrogenic pseudoaneurysm (PSA) is also discussed. A section on the important topic of vascular laboratory accreditation is included. Finally, additional details regarding proper technique for performance of the various vascular tests and procedures are included in the Appendix.