Effects of Semaglutide on Muscle Structure and Function in the SLIM LIVER Study.

BACKGROUND: Semaglutide, a GLP-1 receptor agonist, is highly effective for decreasing weight. Concomitant loss of muscle mass often accompanies weight loss and may have consequences on muscle function. METHODS: This is a secondary analysis from the SLIM LIVER (ACTG A5371) study, a single-arm study of semaglutide in people with HIV (PWH) with metabolic dysfunction-associated steatotic liver disorder (MASLD). Participants received subcutaneous semaglutide for 24 weeks (titrated to 1 mg/week by week 4). Psoas volume and fat fraction were assessed from liver magnetic resonance imaging and physical function by 10-time chair rise test and 4m gait speed. Mean change from baseline to week 24 was estimated with linear regression modeling. RESULTS: 51 PWH enrolled; muscle measures were available from 46 participants. The mean age was 50 (standard deviation [SD] 11) years and BMI 35.5 (5.6) kg/m2, 43% were women, 33% Black, and 39% Hispanic/Latino. Psoas muscle volume decreased by 9.3% (95% confidence interval [CI]: -13.4, -5.2; p<0.001) over 24 weeks but psoas muscle fat did not significantly change (-0.42%, CI: -1.00, 0.17; p=0.16). Chair rise and gait speed had non-significant improvements of 1.27 seconds (CI: -2.7, 0.10) and 0.05 m/sec (CI: -0.01, 0.10), respectively (both p>0.07). The prevalence of slow gait speed (< 1 m/sec) decreased from 63% to 46% (p=0.029). CONCLUSIONS: In PWH receiving low-dose semaglutide for MASLD, despite decreased psoas muscle volume, there was no significant change in physical function. This suggests that function was maintained despite significant loss of muscle concomitant with weight loss.

Supplementing Glycine and N-Acetylcysteine (GlyNAC) in Older Adults Improves Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Inflammation, Physical Function, and Aging Hallmarks: A Randomized Clinical Trial.

BACKGROUND: Elevated oxidative stress (OxS), mitochondrial dysfunction, and hallmarks of aging are identified as key contributors to aging, but improving/reversing these defects in older adults (OA) is challenging. In prior studies, we identified that deficiency of the intracellular antioxidant glutathione (GSH) could play a role and reported that supplementing GlyNAC (combination of glycine and N-acetylcysteine [NAC]) in aged mice improved GSH deficiency, OxS, mitochondrial fatty-acid oxidation (MFO), and insulin resistance (IR). To test whether GlyNAC supplementation in OA could improve GSH deficiency, OxS, mitochondrial dysfunction, IR, physical function, and aging hallmarks, we conducted a placebo-controlled randomized clinical trial. METHODS: Twenty-four OA and 12 young adults (YA) were studied. OA was randomized to receive either GlyNAC (N = 12) or isonitrogenous alanine placebo (N = 12) for 16-weeks; YA (N = 12) received GlyNAC for 2-weeks. Participants were studied before, after 2-weeks, and after 16-weeks of supplementation to assess GSH concentrations, OxS, MFO, molecular regulators of energy metabolism, inflammation, endothelial function, IR, aging hallmarks, gait speed, muscle strength, 6-minute walk test, body composition, and blood pressure. RESULTS: Compared to YA, OA had GSH deficiency, OxS, mitochondrial dysfunction (with defective molecular regulation), inflammation, endothelial dysfunction, IR, multiple aging hallmarks, impaired physical function, increased waist circumference, and systolic blood pressure. GlyNAC (and not placebo) supplementation in OA improved/corrected these defects. CONCLUSION: GlyNAC supplementation in OA for 16-weeks was safe and well-tolerated. By combining the benefits of glycine, NAC and GSH, GlyNAC is an effective nutritional supplement that improves and reverses multiple age-associated abnormalities to promote health in aging humans. Clinical Trials Registration Number: NCT01870193.

Gadolinium-Based Contrast Agents: Updates and Answers to Typical Questions Regarding Gadolinium Use.

Gadolinium-based contrast agents have expanded the diagnostic usefulness and capability of magnetic resonance imaging. Despite their highly favorable safety profile, these agents have been associated with nephrogenic systemic fibrosis in a small number of patients who have advanced kidney disease. Recently, trace amounts of gadolinium deposition in the brain and other organs have been reported after contrast exposure, even in patients with normal renal function. In this review, we provide a brief overview of recent updates and discuss typical clinical situations related to the use of gadolinium-based contrast agents.

Ultrafast Computation of Left Ventricular Ejection Fraction by Using Temporal Intensity Variation in Cine Cardiac Magnetic Resonance.

Cardiac magnetic resonance enables comprehensive cardiac evaluation; however, intense time and labor requirements for data acquisition and processing have discouraged many clinicians from using it. We have developed an alternative image-processing algorithm that requires minimal user interaction: an ultrafast algorithm that computes left ventricular ejection fraction (LVEF) by using temporal intensity variation in cine balanced steady-state free precession (bSSFP) short-axis images, with or without contrast medium. We evaluated the algorithm's performance against an expert observer's analysis for segmenting the LV cavity in 65 study participants (LVEF range, 12%-70%). In 12 instances, contrast medium was administered before cine imaging. Bland-Altman analysis revealed quantitative effects of LV basal, midcavity, and apical morphologic variation on the algorithm's accuracy. Total computation time for the LV stack was <2.5 seconds. The algorithm accurately delineated endocardial boundaries in 1,132 of 1,216 slices (93%). When contours in the extreme basal and apical slices were not adequate, they were replaced with manually drawn contours. The Bland-Altman mean differences were <1.2 mL (0.8%) for end-diastolic volume, <5 mL (6%) for end-systolic volume, and <3% for LVEF. Standard deviation of the difference was ≤4.1% of LV volume for all sections except the midcavity in end-systole (8.3% of end-systolic volume). We conclude that temporal intensity variation-based ultrafast LVEF computation is clinically accurate across a range of LV shapes and wall motions and is suitable for postcontrast cine SSFP imaging. Our algorithm enables real-time processing of cine bSSFP images on a commercial scanner console within 3 seconds in an unobtrusive automated process.

Young athletes: Preventing sudden death by adopting a modern screening approach? A critical review and the opening of a debate.

Preventing sudden cardiac death (SCD) in athletes is a primary duty of sports cardiologists. Current recommendations for detecting high-risk cardiovascular conditions (hr-CVCs) are history and physical examination (H&P)-based. We discuss the effectiveness of H&P-based screening versus more-modern and accurate methods. In this position paper, we review current authoritative statements and suggest a novel alternative: screening MRI (s-MRI), supported by evidence from a preliminary population-based study (completed in 2018), and a prospective, controlled study in military recruits (in development). We present: 1. Literature-Based Comparisons (for diagnosing hr-CVCs): Two recent studies using traditional methods to identify hr-CVCs in >3,000 young athletes are compared with our s-MRI-based study of 5,169 adolescents. 2. Critical Review of Previous Results: The reported incidence of SCD in athletes is presently based on retrospective, observational, and incomplete studies. H&P's screening value seems minimal for structural heart disease, versus echocardiography (which improves diagnosis for high-risk cardiomyopathies) and s-MRI (which also identifies high-risk coronary artery anomalies). Electrocardiography is valuable in screening for potentially high-risk electrophysiological anomalies. 3. Proposed Project : We propose a prospective, controlled study (2 comparable large cohorts: one historical, one prospective) to compare: (1) diagnostic accuracy and resulting mortality-prevention performance of traditional screening methods versus questionnaire/electrocardiography/s-MRI, during 2-month periods of intense, structured exercise (in military recruits, in advanced state of preparation); (2) global costs and cost/efficiency between these two methods. This study should contribute significantly toward a comprehensive understanding of the incidence and causes of exercise-related mortality (including establishing a definition of hr-CVCs) while aiming to reduce mortality.

Supplementing Glycine and N-acetylcysteine (GlyNAC) in Aging HIV Patients Improves Oxidative Stress, Mitochondrial Dysfunction, Inflammation, Endothelial Dysfunction, Insulin Resistance, Genotoxicity, Strength, and Cognition: Results of an Open-Label Clinical Trial.

Background: Patients with HIV (PWH) develop geriatric comorbidities, including functional and cognitive decline at a younger age. However, contributing mechanisms are unclear and interventions are lacking. We hypothesized that deficiency of the antioxidant protein glutathione (GSH) contributes to multiple defects representing premature aging in PWH, and that these defects could be improved by supplementing the GSH precursors glycine and N-acetylcysteine (GlyNAC). Methods: We conducted an open label clinical trial where eight PWH and eight matched uninfected-controls were studied at baseline. PWH were studied again 12-weeks after receiving GlyNAC, and 8-weeks after stopping GlyNAC. Controls did not receive supplementation. Outcome measures included red-blood cell and muscle GSH concentrations, mitochondrial function, mitophagy and autophagy, oxidative stress, inflammation, endothelial function, genomic damage, insulin resistance, glucose production, muscle-protein breakdown rates, body composition, physical function and cognition. Results: PWH had significant defects in measured outcomes, which improved with GlyNAC supplementation. However, benefits receded after stopping GlyNAC. Conclusions: This open label trial finds that PWH have premature aging based on multiple biological and functional defects, and identifies novel mechanistic explanations for cognitive and physical decline. Nutritional supplementation with GlyNAC improves comorbidities suggestive of premature aging in PWH including functional and cognitive decline, and warrants additional investigation.

Multidetector Computed Tomography (MDCT) Angiography in the Pre-Procedural Assessment of Patients Undergoing Transcatheter Aortic Valve Replacement.

Transcatheter aortic valve replacement (TAVR) initially emerged as an alternative option to surgical aortic valve replacement (SAVR) for patients with severe aortic stenosis who were considered either inoperable or high-risk for surgery. However, since its advent the role of TAVR has been continuously evolving on the basis of clinical trials which showed that TAVR is non-inferior to SAVR in patients with moderate as well as low-risk for surgery. Because of recent technological advances, multidetector computer tomography (MDCT) is inherently suitable for the pre-procedural assessment of patients being considered for TAVR within a very short imaging time, MDCT can measure the diameter of the aortic annulus, provide detailed information regarding the status of the entire thoracoabdominal aorta, and assess the caliber of the peripheral vasculature used for transcatheter heart valve delivery. This information helps interventionists make optimal pre-procedural decisions and avoid complications. To familiarize non-imaging specialists with the role of MDCT in TAVR, we provide a concise overview of our approach to using this modality for the pre-procedural assessment of TAVR candidates.

Mitral Valve Flow and Myocardial Motion Assessed with Dual-Echo Dual-Velocity Cardiac MRI.

PURPOSE: To develop a dual-echo phase-contrast (DEPC) MRI approach with which each echo is acquired by using a different velocity sensitivity within one repetition time (TR) and demonstrate the feasibility of this approach to measure transmitral blood flow (E) and myocardial tissue (E m) velocities. MATERIALS AND METHODS: The flow across tubes of known diameter was measured by using the proposed DEPC method and compared with flowmeter measurements and theoretic predictions. Then, with both the DEPC MRI sequence and the conventional single-echo phase-contrast (SEPC) MRI sequence, E, E m, and E/E m were measured in six healthy volunteers (mean age, 49 years ± 13 [standard deviation]) and eight patients (mean age, 54 years ± 15) being evaluated for cardiac disease. Differences between the DEPC and conventional SEPC MRI methods were assessed by percent error, Pearson correlation, and Bland-Altman analyses. RESULTS: Velocities measured in vitro and in vivo by using the SEPC and DEPC MRI approaches were well correlated (r 2 > 0.97), with negligible bias (<0.5 cm/sec) and comparable velocity-to-noise ratios. Imaging times were approximately 19% shorter with the DEPC method (TR, 5.7 msec) than with the SEPC method (TR, 2.8 msec ± 4.2) (P < .05). CONCLUSION: The proposed DEPC method was sensitive to two velocity regimes within a single TR, resulting in a shorter imaging time compared with the imaging time in conventional SEPC MRI. Preliminary human study results suggest the feasibility of using this approach to estimate E/E m.Supplemental material is available for this article.© RSNA, 2020.

High frame rate cardiac cine MRI for the evaluation of diastolic function and its direct correlation with echocardiography.

BACKGROUND: Breath-hold cine MR is the method of choice for evaluating left ventricular (LV) systolic function; however, the evaluation of diastolic function remains in the domain of high frame rate echocardiography. Thus, a cine MR technique for simultaneously evaluating LV systolic and diastolic function would be clinically valuable. PURPOSE: To test the feasibility of extracting indices that characterize LV diastolic function from high frame rate cine MR. STUDY TYPE: Single center, prospective. POPULATION: Asymptomatic volunteers (N = 24; age 45.8 ± 12.3 years). FIELD STRENGTH/SEQUENCE: High frame rate (70 fps) cine MR and phase-contrast MR during free breathing were acquired at 1.5T. ASSESSMENT: The following MR-based LV filling metrics were extracted from LV volume changes during the cardiac cycle: 1) the volume-rate ratio, REFP /RLFP (ratio of the peak LV filling rate during the early filling period [EFP] to that during the late filling period [LFP]); and 2) the volume ratio, VEFP /VLFP (the ratio of cumulative LV volume change between the EFP and LFP). These metrics were then compared with traditional transmitral blood flow-based MR and echocardiographic indices. The effect of temporal resolution on these metrics was also evaluated. STATISTICAL TESTS: Bland-Altman and linear regression analyses were used to evaluate the performance of the proposed metrics against traditional indices of diastolic function. RESULTS: The REFP /RLFP and VEFP /VLFP correlated well with E/AQ-flow (r 2 = 0.66 and 0.54, respectively) and E/Aecho (r 2 = 0.58 and 0.49, respectively). Systolic indices remained robust (<3% error) for frame rates ≥20 fps. Although the proposed VEFP /VLFP was robust (<5% error) up to 25 fps, the proposed volume-rate diastolic function metrics were less reliable (>8% error) for frame rates below 35 fps. DATA CONCLUSION: In asymptomatic volunteers, cardiac cine MR images acquired at frame rates >35 fps can be used to extract LV diastolic function indices from the temporal changes in LV volume. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage: 1 J. Magn. Reson. Imaging 2019;50:1571-1582.

High-Risk Cardiovascular Conditions in Sports-Related Sudden Death: Prevalence in 5,169 Schoolchildren Screened via Cardiac Magnetic Resonance.

Improving preparticipation screening of candidates for sports necessitates establishing the prevalence of high-risk cardiovascular conditions (hr-CVC) that predispose young people to sudden cardiac death (SCD). Our accurate, novel protocol chiefly involved the use of cardiac magnetic resonance (CMR) to estimate this prevalence. Middle and high school students from a general United States population were screened by means of questionnaires, resting electrocardiograms, and CMR to determine the prevalence of 3 types of hr-CVC: electrocardiographic abnormalities, cardiomyopathies, and anomalous coronary artery origin from the opposite sinus with intramural coronary course (ACAOS-IM). We examined the range of normal left ventricular size and function in the main study cohort (schoolchildren 11-14 yr old). We defined diagnostic criteria for hr-CVC and compared the cardiac measurements of these younger participants with those of older children whom we examined (age, 15-18 yr). From 5,169 completed diagnostic studies (mean participant age, 13.06 ± 1.78 yr), CMR results revealed 76 previously undiagnosed cases of hr-CVC (1.47% of the total cohort): 11 of dilated cardiomyopathy (14.5%), 3 of nonobstructive hypertrophic cardiomyopathy (3.9%), 23 ACAOS-IM cases (30.3%; 6 left-ACAOS and 17 right-ACAOS), 4 Wolff-Parkinson-White patterns (5.3%), 34 prolonged QT intervals (44.7%), and 1 Brugada pattern (1.3%). Cardiomyopathies were significantly more prevalent in the older children. Of note, we identified 959 cases (18.5%) of left ventricular noncompaction. If our estimate is accurate, only 1.47% of school-age sports participants will need focused secondary evaluations; the rest can probably be reassured about their cardiac health after one 30-minute screening study.

A New High-Performance Gadonanotube-Polymer Hybrid Material for Stem Cell Labeling and Tracking by MRI.

A gentle, rapid method has been developed to introduce a polyacrylic acid (PAA) polymer coating on the surface of gadonanotubes (GNTs) which significantly increases their dispersibility in water without the need of a surfactant. As a result, the polymer, with its many carboxylic acid groups, coats the surface of the GNTs to form a new GNT-polymer hybrid material (PAA-GNT) which can be highly dispersed in water (ca. 20 mg·mL-1) at physiological pH. When dispersed in water, the new PAA-GNT material is a powerful MRI contrast agent with an extremely short water proton spin-lattice relaxation time (T1) which results in a T1-weighted relaxivity of 150 mM-1·s-1 per Gd3+ ion at 1.5 T. Furthermore, the PAA-GNTs have been used to safely label porcine bone-marrow-derived mesenchymal stem cells for magnetic resonance imaging. The labeled cells display excellent image contrast in phantom imaging experiments, and transmission electron microscopy images of the labeled cells reveal the presence of highly dispersed PAA-GNTs within the cytoplasm with 1014 Gd3+ ions per cell.

Two-center clinical validation and quantitative assessment of respiratory triggered retrospectively cardiac gated balanced-SSFP cine cardiovascular magnetic resonance imaging in adults.

BACKGROUND: Breath-hold (BH) requirement remains the limiting factor on the spatio-temporal resolution and coverage of the cine balanced steady-state free precession (bSSFP) cardiovascular magnetic resonance (CMR) imaging. In this prospective two-center clinical trial, we validated the performance of a respiratory triggered (RT) bSSFP cine sequence for evaluation of biventricular function. METHODS: Our study included 23 asymptomatic healthy subjects and 60 consecutive patients from Institute A (n = 39) and Institute B (n = 21) referred for a clinically indicated CMR study. We implemented a RT sequence with a respiratory synchronized drive to steady state (SS) of bSSFP signal, before the commencement of image data acquisition with prospective cardiac arrhythmia rejection and retrospectively cardiac gated reconstruction in real-time. Left (LV) and right (RV) ventricular function and LV mass were evaluated by using RT-bSSFP and conventional BH-bSSFP sequences with one cardiac cycle for SS preparation keeping all the imaging parameters identical. The performance of the sequences was evaluated by using quantitative and semi-quantitative metrics. RESULTS: Global LV and RV functional parameters and LV mass obtained from the RT-bSSFP and BH-bSSFP sequences were in good agreement. Quantitative metrics designed to capture fluctuation in SS signal intensity showed no significant difference between sequences. In addition, blood-to-myocardial contrast was nearly identical between sequences. The combined clinical score for image quality was excellent or good for 100% of cases with the BH-bSSFP and 83% of cases with the RT-bSSFP sequence. The de facto image acquisition time for RT-bSSFP was statistically significantly longer than that for conventional BH-bSSFP (7.9 ± 3.4 min vs. 5.1 ± 2.6 min). CONCLUSIONS: Cine RT-bSSFP is an alternative for evaluating global biventricular function with contrast and spatio-temporal resolutions that are similar to those attained by using the BH-bSSFP sequence, albeit with a modest time penalty and a small reduction in image quality.

Tissue characterization of uterine fibroids with an intravoxel incoherent motion model: The need for T2 correction.

BACKGROUND: Diminished signal intensity of uterine fibroids in T2 -weighted images is routinely used as a qualitative marker of fibroid hypoperfusion. However, quantitative classification of fibroid perfusion with intravoxel incoherent motion (IVIM) model-based metrics is not yet clinically accepted. PURPOSE: To investigate the influence of T2 correction on the estimation of IVIM model parameters for characterizing uterine fibroid tissue. STUDY TYPE: Prospective. POPULATION: Fourteen women with 41 fibroids (12 Type I and 29 Type II, per Funaki classification) underwent diffusion-weighted imaging and T2 mapping. FIELD STRENGTH: Diffusion-weighted images (b values: 0, 20, 40, 60, 100, 200, 400, 600, 800, 1000 s/mm2 ) and T2 maps were obtained at 1.5T. ASSESSMENT: The effect of uterine fibroid T2 variation on IVIM model parameters (diffusion coefficient, perfusion coefficient, and perfusion volume fraction) were numerically modeled and experimentally evaluated without (D, D*, f) and with (Dc , D c * , fc ) T2 correction. The relationship of T2 with D and the T2 -corrected perfusion volume fraction (fc ) was also examined. STATISTICAL TEST: D-values and f-values estimated with and without T2 correction were compared by using a two-tailed Student's t-test. RESULTS: Type II fibroids had higher D and f than Type I fibroids, but the differences were not significant (Type I vs. Type II, D: 0.83 ± 0.20 vs. 0.80 ± 0.25 mm2 /s, P = 0.78; f: 23.64 ± 4.87% vs. 25.27 ± 7.46%, P = 0.49). For Type I and Type II fibroids, fc was lower than f, and fc of Type II fibroids was significantly higher than that of Type I fibroids (Type I vs. Type II, fc : 7.80 ± 1.88% vs. 11.82 ± 4.13%, P = 0.003). Both D and fc exponentially increased with the increase of fibroid T2 as functions: D c ( T 2 ) = - 1.52 × 10 - 3 ⋅ e - 3.42 T 2 290 + 1.84 × 10 - 3 and f c ( T 2 ) = - 0.2336 ⋅ e - 3.217 T 2 290 + 0.2269 , respectively. D asymptotically approached 1.79 × 10-3 mm2 /s, and fc approached 21.74%. DATA CONCLUSION: T2 correction is important when using IVIM-based models to characterize uterine fibroid tissue. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;48:994-1001.

Evaluation of Cell Therapy on Exercise Performance and Limb Perfusion in Peripheral Artery Disease: The CCTRN PACE Trial (Patients With Intermittent Claudication Injected With ALDH Bright Cells).

BACKGROUND: Atherosclerotic peripheral artery disease affects 8% to 12% of Americans >65 years of age and is associated with a major decline in functional status, increased myocardial infarction and stroke rates, and increased risk of ischemic amputation. Current treatment strategies for claudication have limitations. PACE (Patients With Intermittent Claudication Injected With ALDH Bright Cells) is a National Heart, Lung, and Blood Institute-sponsored, randomized, double-blind, placebo-controlled, phase 2 exploratory clinical trial designed to assess the safety and efficacy of autologous bone marrow-derived aldehyde dehydrogenase bright (ALDHbr) cells in patients with peripheral artery disease and to explore associated claudication physiological mechanisms. METHODS: All participants, randomized 1:1 to receive ALDHbr cells or placebo, underwent bone marrow aspiration and isolation of ALDHbr cells, followed by 10 injections into the thigh and calf of the index leg. The coprimary end points were change from baseline to 6 months in peak walking time (PWT), collateral count, peak hyperemic popliteal flow, and capillary perfusion measured by magnetic resonance imaging, as well as safety. RESULTS: A total of 82 patients with claudication and infrainguinal peripheral artery disease were randomized at 9 sites, of whom 78 had analyzable data (57 male, 21 female patients; mean age, 66±9 years). The mean±SEM differences in the change over 6 months between study groups for PWT (0.9±0.8 minutes; 95% confidence interval [CI] -0.6 to 2.5; P=0.238), collateral count (0.9±0.6 arteries; 95% CI, -0.2 to 2.1; P=0.116), peak hyperemic popliteal flow (0.0±0.4 mL/s; 95% CI, -0.8 to 0.8; P=0.978), and capillary perfusion (-0.2±0.6%; 95% CI, -1.3 to 0.9; P=0.752) were not significant. In addition, there were no significant differences for the secondary end points, including quality-of-life measures. There were no adverse safety outcomes. Correlative relationships between magnetic resonance imaging measures and PWT were not significant. A post hoc exploratory analysis suggested that ALDHbr cell administration might be associated with an increase in the number of collateral arteries (1.5±0.7; 95% CI, 0.1-2.9; P=0.047) in participants with completely occluded femoral arteries. CONCLUSIONS: ALDHbr cell administration did not improve PWT or magnetic resonance outcomes, and the changes in PWT were not associated with the anatomic or physiological magnetic resonance imaging end points. Future peripheral artery disease cell therapy investigational trial design may be informed by new anatomic and perfusion insights. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01774097.

Baseline assessment and comparison of arterial anatomy, hyperemic flow, and skeletal muscle perfusion in peripheral artery disease: The Cardiovascular Cell Therapy Research Network "Patients with Intermittent Claudication Injected with ALDH Bright Cells" (CCTRN PACE) study.

BACKGROUND: Peripheral artery disease (PAD) is important to public health as a major contributor to cardiovascular morbidity and mortality. Recent developments in magnetic resonance imaging (MRI) techniques permit improved assessment of PAD anatomy and physiology, and may serve as surrogate end points after proangiogenic therapies. METHODS: The PACE study is a randomized, double-blind, placebo-controlled clinical trial designed to assess the physiologic impact and potential clinical efficacy of autologous bone marrow-derived ALDHbr stem cells. The primary MRI end points of the study are as follows: (1) total collateral count, (2) calf muscle plasma volume (a measure of capillary perfusion) by dynamic contrast-enhanced MRI, and (3) peak hyperemic popliteal flow by phase-contrast MRI (PC-MRI). RESULTS: The interreader and intrareader and test-retest results demonstrated good-to-excellent reproducibility (interclass correlation coefficient range 0.61-0.98) for all magnetic resonance measures. The PAD participants (n=82) had lower capillary perfusion measured by calf muscle plasma volume (3.8% vs 5.6%) and peak hyperemic popliteal flow (4.1 vs 13.5mL/s) as compared with the healthy participants (n=16), with a significant level of collateralization. CONCLUSIONS: Reproducibility of the MRI primary end points in PACE was very good to excellent. The PAD participants exhibited decreased calf muscle capillary perfusion as well as arterial flow reserve when compared with healthy participants. The MRI tools used in PACE may advance PAD science by enabling accurate measurement of PAD microvascular anatomy and perfusion before and after stem cell or other PAD therapies.