Impact of supervised exercise on skeletal muscle blood flow and vascular function measured with MRI in patients with peripheral artery disease.

Supervised exercise is a common therapeutic intervention for patients with peripheral artery disease (PAD), however, the mechanism underlying the improvement in claudication symptomatology is not completely understood. The hypothesis that exercise improves microvascular blood flow is herein tested via temporally resolved magnetic resonance imaging (MRI) measurement of blood flow and oxygenation dynamics during reactive hyperemia in the leg with the lower ankle-brachial index. One hundred and forty-eight subjects with PAD were prospectively assigned to standard medical care or 3 mo of supervised exercise therapy. Before and after the intervention period, subjects performed a graded treadmill walking test, and MRI data were collected with Perfusion, Intravascular Venous Oxygen saturation, and T2* (PIVOT), a method that simultaneously quantifies microvascular perfusion, as well as relative oxygenation changes in skeletal muscle and venous oxygen saturation in a large draining vein. The 3-mo exercise intervention was associated with an improvement in peak walking time (64% greater in those randomized to the exercise group at follow-up, P < 0.001). Significant differences were not observed in the MRI measures between the subjects randomized to exercise therapy versus standard medical care based on an intention-to-treat analysis. However, the peak postischemia perfusion averaged across the leg between baseline and follow-up visits increased by 10% (P = 0.021) in participants that were adherent to the exercise protocol (completed >80% of prescribed exercise visits). In this cohort of adherent exercisers, there was no difference in the time to peak perfusion or oxygenation metrics, suggesting that there was no improvement in microvascular function nor changes in tissue metabolism in response to the 3-mo exercise intervention.NEW & NOTEWORTHY Supervised exercise interventions can improve symptomatology in patients with peripheral artery disease, but the underlying mechanism remains unclear. Here, MRI was used to evaluate perfusion, relative tissue oxygenation, and venous oxygen saturation in response to cuff-induced ischemia. Reactive hyperemia responses were measured before and after 3 mo of randomized supervised exercise therapy or standard medical care. Those participants who were adherent to the exercise regimen had a significant improvement in peak perfusion.

Lessons From the Testosterone Trials.

The Testosterone Trials (TTrials) were a coordinated set of seven placebo-controlled, double-blind trials in 788 men with a mean age of 72 years to determine the efficacy of increasing the testosterone levels of older men with low testosterone. Testosterone treatment increased the median testosterone level from unequivocally low at baseline to midnormal for young men after 3 months and maintained that level until month 12. In the Sexual Function Trial, testosterone increased sexual activity, sexual desire, and erectile function. In the Physical Function Trial, testosterone did not increase the distance walked in 6 minutes in men whose walk speed was slow; however, in all TTrial participants, testosterone did increase the distance walked. In the Vitality Trial, testosterone did not increase energy but slightly improved mood and depressive symptoms. In the Cognitive Function Trial, testosterone did not improve cognitive function. In the Anemia Trial, testosterone increased hemoglobin in both men who had anemia of a known cause and in men with unexplained anemia. In the Bone Trial, testosterone increased volumetric bone mineral density and the estimated strength of the spine and hip. In the Cardiovascular Trial, testosterone increased the coronary artery noncalcified plaque volume as assessed using computed tomographic angiography. Although testosterone was not associated with more cardiovascular or prostate adverse events than placebo, a trial of a much larger number of men for a much longer period would be necessary to determine whether testosterone increases cardiovascular or prostate risk.

Vascular ossification: Pathology, mechanisms, and clinical implications.

In recent years, the mechanisms and clinical significance of vascular calcification have been increasingly investigated. For over a century, however, pathologists have recognized that vascular calcification is a form of heterotopic ossification. In this review, we aim to describe the pathology and molecular processes of vascular ossification, to characterize its clinical significance and treatment options, and to elucidate areas that require further investigation. The molecular mechanisms of vascular ossification involve the activation of regulators including bone morphogenic proteins and chondrogenic transcription factors and the loss of mineralization inhibitors like fetuin-A and pyrophosphate. Although few studies have examined the gross pathology of vascular ossification, the presence of these molecular regulators and evidence of microfractures and cartilage have been demonstrated on heart valves and atherosclerotic plaques. These changes are often triggered by common inflammatory and metabolic disorders like diabetes, hyperlipidemia, and chronic kidney disease. The increasing prevalence of these diseases warrants further research into the clinical significance of vascular ossification and future treatment options.

The Effect of Testosterone on Cardiovascular Biomarkers in the Testosterone Trials.

Context: Studies of the possible cardiovascular risk of testosterone treatment are inconclusive. Objective: To determine the effect of testosterone treatment on cardiovascular biomarkers in older men with low testosterone. Design: Double-blind, placebo-controlled trial. Setting: Twelve academic medical centers in the United States. Participants: In all, 788 men ≥65 years old with an average of two serum testosterone levels <275 ng/dL who were enrolled in The Testosterone Trials. Intervention: Testosterone gel, the dose adjusted to maintain the testosterone level in the normal range for young men, or placebo gel for 12 months. Main Outcome Measures: Serum markers of cardiovascular risk, including lipids and markers of glucose metabolism, fibrinolysis, inflammation, and myocardial damage. Results: Compared with placebo, testosterone treatment significantly decreased total cholesterol (adjusted mean difference, -6.1 mg/dL; P < 0.001), high-density lipoprotein cholesterol (adjusted mean difference, -2.0 mg/dL; P < 0.001), and low-density lipoprotein cholesterol (adjusted mean difference, -2.3 mg/dL; P = 0.051) from baseline to month 12. Testosterone also slightly but significantly decreased fasting insulin (adjusted mean difference, -1.7 µIU/mL; P = 0.02) and homeostatic model assessment‒insulin resistance (adjusted mean difference, -0.6; P = 0.03). Testosterone did not change triglycerides, d-dimer, C-reactive protein, interleukin 6, troponin, glucose, or hemoglobin A1c levels more than placebo. Conclusions and Relevance: Testosterone treatment of 1 year in older men with low testosterone was associated with small reductions in cholesterol and insulin but not with other glucose markers, markers of inflammation or fibrinolysis, or troponin. The clinical importance of these findings is unclear and requires a larger trial of clinical outcomes.

Simultaneous measurement of macro- and microvascular blood flow and oxygen saturation for quantification of muscle oxygen consumption.

PURPOSE: To investigate the relationship between blood flow and oxygen consumption in skeletal muscle, a technique called "Velocity and Perfusion, Intravascular Venous Oxygen saturation and T2*" (vPIVOT) is presented. vPIVOT allows the quantification of feeding artery blood flow velocity, perfusion, draining vein oxygen saturation, and muscle T2*, all at 4-s temporal resolution. Together, the measurement of blood flow and oxygen extraction can yield muscle oxygen consumption ( V˙O2) via the Fick principle. METHODS: In five subjects, vPIVOT-derived results were compared with those obtained from stand-alone sequences during separate ischemia-reperfusion paradigms to investigate the presence of measurement bias. Subsequently, in 10 subjects, vPIVOT was applied to assess muscle hemodynamics and V˙O2 following a bout of dynamic plantar flexion contractions. RESULTS: From the ischemia-reperfusion paradigm, no significant differences were observed between data from vPIVOT and comparison sequences. After exercise, the macrovascular flow response reached a maximum 8 ± 3 s after relaxation; however, perfusion in the gastrocnemius muscle continued to rise for 101 ± 53 s. Peak V˙O2 calculated based on mass-normalized arterial blood flow or perfusion was 15.2 ± 6.7 mL O2 /min/100 g or 6.0 ± 1.9 mL O2 /min/100 g, respectively. CONCLUSIONS: vPIVOT is a new method to measure blood flow and oxygen saturation, and therefore to quantify muscle oxygen consumption. Magn Reson Med 79:846-855, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Effects of exercise training on calf muscle oxygen extraction and blood flow in patients with peripheral artery disease.

We employed near-infrared optical techniques, diffuse correlation spectroscopy (DCS), and frequency-domain near-infrared spectroscopy (FD-NIRS) to test the hypothesis that supervised exercise training increases skeletal muscle microvascular blood flow and oxygen extraction in patients with peripheral artery disease (PAD) who experience claudication. PAD patients ( n = 64) were randomly assigned to exercise and control groups. Patients in the exercise group received 3 mo of supervised exercise training. Calf muscle blood flow and oxygen extraction were optically monitored before, during, and after performance of a graded treadmill protocol at baseline and at 3 mo in both groups. Additionally, measurements of the ankle-brachial index (ABI) and peak walking time (PWT) to maximal claudication were made during each patient visit. Supervised exercise training was found to increase the maximal calf muscle blood flow and oxygen extraction levels during treadmill exercise by 29% (13%, 50%) and 8% (1%, 12%), respectively [ P < 0.001; median (25th percentile, 75th percentile)]. These improvements across the exercise group population were significantly higher than corresponding changes in the control group ( P < 0.004). Exercise training also increased PWT by 49% (18%, 101%) ( P = 0.01). However, within statistical error, the ABI, resting calf muscle blood flow and oxygen extraction, and the recovery half-time for hemoglobin\myoglobin desaturation following cessation of maximal exercise were not altered by exercise training. The concurrent monitoring of both blood flow and oxygen extraction with the hybrid DCS/FD-NIRS instrument revealed enhanced muscle oxidative metabolism during physical activity from exercise training, which could be an underlying mechanism for the observed improvement in PWT. NEW & NOTEWORTHY We report on noninvasive optical measurements of skeletal muscle blood flow and oxygen extraction dynamics before/during/after treadmill exercise in peripheral artery disease patients who experience claudication. The measurements tracked the effects of a 3-mo supervised exercise training protocol and revealed that supervised exercise training improved patient ability to increase microvascular calf muscle blood flow and oxygen extraction during physical activity.

Carotid Artery Wall Thickness in Obese and Nonobese Adults With Obstructive Sleep Apnea Before and Following Positive Airway Pressure Treatment.

Study objectives: Debate persists as to whether obstructive sleep apnea (OSA) is an independent risk factor for atherosclerosis. The purpose of this study was to compare carotid intima-media thickness (IMT), an early sign of atherosclerosis, in obese and nonobese adults with OSA before and following positive airway pressure (PAP) treatment. Methods: A total of 206 adults newly diagnosed with OSA with an apnea-hypopnea index (AHI) of 15-75 events/hour and 53 controls with AHI <10 were studied. Waist circumference was used to classify participants as obese and nonobese. Bilateral common carotid artery B-mode ultrasound was performed at baseline to assess IMT, arterial diameter, arterial-wall mass, and circumferential wall stress. Measurements were repeated in 118 participants with OSA who completed a 4-month PAP treatment and had an average daily use over that period of ≥4 hours/day. Results: No significant differences in carotid IMT, diameter, or arterial-wall mass were present at baseline between participants with OSA and controls stratified by waist circumference, after adjusting for other cardiovascular risk factors. In participants with OSA, who had adequate PAP adherence over the 4-month treatment, carotid artery diameter significantly increased (mean change [95% confidence interval] = 0.13 [0.06, 0.20] mm; p = .0004), but no significant changes in carotid IMT, arterial-wall mass, and circumferential stress were observed in obese and nonobese participants. Conclusions: Regardless of obesity status, carotid IMT is not increased in adults with moderate to severe OSA versus controls and does not change following 4 months of PAP treatment.

Self-Reported Health and Outcomes in Patients With Stable Coronary Heart Disease.

BACKGROUND: The major determinants and prognostic importance of self-reported health in patients with stable coronary heart disease are uncertain. METHODS AND RESULTS: The STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial randomized 15 828 patients with stable coronary heart disease to treatment with darapladib or placebo. At baseline, 98% of participants completed a questionnaire that included the question, "Overall, how do you feel your general health is now?" Possible responses were excellent, very good, good, average, and poor. Adjudicated major adverse cardiac events, which included cardiovascular death, myocardial infarction, and stroke, were evaluated by Cox regression during 3.7 years of follow-up for participants who reported excellent or very good health (n=2304), good health (n=6863), and average or poor health (n=6361), before and after adjusting for 38 covariates. Self-reported health was most strongly associated with geographic region, depressive symptoms, and low physical activity (P<0.0001 for all). Poor/average compared with very good/excellent self-reported health was independently associated with major adverse cardiac events (hazard ratio [HR]: 2.30 [95% confidence interval (CI), 1.92-2.76]; adjusted HR: 1.83 [95% CI, 1.51-2.22]), cardiovascular mortality (HR: 4.36 [95% CI, 3.09-6.16]; adjusted HR: 2.15 [95% CI, 1.45-3.19]), and myocardial infarction (HR: 1.87 [95% CI, 1.46-2.39]; adjusted HR: 1.68 [95% CI, 1.25-2.27]; P<0.0002 for all). CONCLUSIONS: Self-reported health is strongly associated with geographical region, mood, and physical activity. In a global coronary heart disease population, self-reported health was independently associated with major cardiovascular events and mortality beyond what is measurable by established risk indicators. CLINICAL TRIAL REGISTRATION: URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00799903.

Catechins as Potential Mediators of Cardiovascular Health.

The impact of diet on cardiovascular disease has become an increasingly relevant topic as ongoing epidemiological evidence continues to demonstrate clear associations with disease burden and mortality. Certain diets, such as those high in sodium and saturated fat, are associated with cardiovascular disease states, while other diets can be cardioprotective. However, there is limited knowledge on how the micro- and macronutrients within such cardioprotective diets afford their benefits. One such micronutrient is the catechin class, which are naturally occurring compounds in plant foods, such as teas, cocoa, wine, pears, and apples. Recent evidence reveals that catechins may be a key mediator in cardiovascular health via mechanisms of blood pressure reduction, flow-mediated vasodilation, and atherosclerosis attenuation. This review evaluates the current literature on the interplay between catechins and cardiovascular disease, which may have important implications for nutrition counseling and pharmaceutical drug development.

Testosterone Treatment and Coronary Artery Plaque Volume in Older Men With Low Testosterone.

Importance: Recent studies have yielded conflicting results as to whether testosterone treatment increases cardiovascular risk. Objective: To test the hypothesis that testosterone treatment of older men with low testosterone slows progression of noncalcified coronary artery plaque volume. Design, Setting, and Participants: Double-blinded, placebo-controlled trial at 9 academic medical centers in the United States. The participants were 170 of 788 men aged 65 years or older with an average of 2 serum testosterone levels lower than 275 ng/dL (82 men assigned to placebo, 88 to testosterone) and symptoms suggestive of hypogonadism who were enrolled in the Testosterone Trials between June 24, 2010, and June 9, 2014. Intervention: Testosterone gel, with the dose adjusted to maintain the testosterone level in the normal range for young men, or placebo gel for 12 months. Main Outcomes and Measures: The primary outcome was noncalcified coronary artery plaque volume, as determined by coronary computed tomographic angiography. Secondary outcomes included total coronary artery plaque volume and coronary artery calcium score (range of 0 to >400 Agatston units, with higher values indicating more severe atherosclerosis). Results: Of 170 men who were enrolled, 138 (73 receiving testosterone treatment and 65 receiving placebo) completed the study and were available for the primary analysis. Among the 138 men, the mean (SD) age was 71.2 (5.7) years, and 81% were white. At baseline, 70 men (50.7%) had a coronary artery calcification score higher than 300 Agatston units, reflecting severe atherosclerosis. For the primary outcome, testosterone treatment compared with placebo was associated with a significantly greater increase in noncalcified plaque volume from baseline to 12 months (from median values of 204 mm3 to 232 mm3 vs 317 mm3 to 325 mm3, respectively; estimated difference, 41 mm3; 95% CI, 14 to 67 mm3; P = .003). For the secondary outcomes, the median total plaque volume increased from baseline to 12 months from 272 mm3 to 318 mm3 in the testosterone group vs from 499 mm3 to 541 mm3 in the placebo group (estimated difference, 47 mm3; 95% CI, 13 to 80 mm3; P = .006), and the median coronary artery calcification score changed from 255 to 244 Agatston units in the testosterone group vs 494 to 503 Agatston units in the placebo group (estimated difference, -27 Agatston units; 95% CI, -80 to 26 Agatston units). No major adverse cardiovascular events occurred in either group. Conclusions and Relevance: Among older men with symptomatic hypogonadism, treatment with testosterone gel for 1 year compared with placebo was associated with a significantly greater increase in coronary artery noncalcified plaque volume, as measured by coronary computed tomographic angiography. Larger studies are needed to understand the clinical implications of this finding. Trial Registration: clinicaltrials.gov Identifier: NCT00799617.

Vascular Health Profile predicts cardiovascular outcomes in patients with diabetes.

BACKGROUND: We previously reported the development of a novel high dimensional cytomic assay, the Vascular Health Profile (VHP) based on measurements of angiogenic circulating hematopoietic stem and progenitor cells (CHSPCAng ) and extracellular vesicles (EVs), that discovered a unique signature, differentiating the vascular status of diabetics and normal healthy controls. Here, we present data from a 3-year follow-up to evaluate the power of the VHP to identify individuals at risk for cardiovascular (CV) events. METHODS: The original data were generated as previously described by measuring a broad panel of progenitor cells and EVs and profiled using cytometric fingerprinting. Subjects were classified into groups according to the occurrence of adjudicated CV events including myocardial infarction, stroke, major adverse cardiovascular events, revascularization, and irregular rhythm. Cross-validated Linear Discriminate Analysis (LDA) models were constructed and used to predict the occurrence of events, and were evaluated for predictive accuracy (AUC, area under the curve) using receiver operating characteristic (ROC) analysis. RESULTS: Over the period of this analysis, follow-up data was obtained on 87 subjects, with 32 events occurring overall, and only in the diabetic group. In all cases, the VHP added significant predictive power, in the form of ROC analysis, for all evaluated outcomes with the exception of irregular rhythm. CONCLUSIONS: The VHP, a relatively simple blood test, can provide sensitive and clinically relevant information on the vascular status of a patient that may be useful for a variety of applications including drug development, clinical risk assessment, and companion diagnostics. © 2015 International Clinical Cytometry Society.

Growth Differentiation Factor 15 Predicts All-Cause Morbidity and Mortality in Stable Coronary Heart Disease.

BACKGROUND: Higher growth differentiation factor 15 (GDF-15) concentrations are associated with cardiovascular (CV) and non-CV morbidity and mortality. However, information on associations between GDF-15 and the risk of specific CV and non-CV events in stable coronary heart disease (CHD) patients is limited. METHODS: In 14 577 patients with stable CHD participating in the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy Trial (STABILITY), GDF-15 and other prognostic biomarkers (N-terminal pro-B-type natriuretic peptide, high-sensitivity troponin T, cystatin C, and high-sensitivity C-reactive protein) were measured. In adjusted Cox regression models, the associations between GDF-15 and the composite CV end point [CV death, myocardial infarction (MI), and stroke], as well as other CV and non-CV events, were assessed. RESULTS: The median concentration (interquartile range) of GDF-15 at baseline was 1253 (915-1827) ng/L. The hazard ratio for the composite end point for the highest compared to the lowest quartile of GDF-15 was 1.8 (95% CI, 1.5-2.2); for CV death, 2.63 (1.9-3.6); for sudden death, 3.06 (1.9-4.8); for heart failure (HF) death, 4.3 (1.3-14); for cancer death, 2.5 (1.3-4.7); for hospitalization for HF, 5.8 (3.2-10); for MI 1.4 (95% CI, 1.1-1.9); and for stroke, 1.8 (95% CI, 1.1-2.8). After adjustment for other prognostic biomarkers, GDF-15 remained significantly associated with all outcomes except for MI. CONCLUSIONS: In stable CHD, GDF-15 was independently associated with CV, non-CV, and cancer mortality, as well as with MI and stroke. When also adjusting for other prognostic biomarkers, the associations to all fatal and nonfatal events were maintained except for MI. Information on GDF-15, therefore, might be helpful when assessing the risk of adverse outcomes in patients with stable CHD. ClinicalTrials.gov Identifier: NCT00799903.

Pathogenesis and Risk Factors for Cerebral Infarct After Surgical Aortic Valve Replacement.

BACKGROUND AND PURPOSE: Stroke is a potentially devastating complication of cardiac surgery. Identifying predictors of radiographic infarct may lead to improved stroke prevention for surgical patients. METHODS: We reviewed 129 postoperative brain magnetic resonance imagings from a prospective study of patients undergoing surgical aortic valve replacement. Acute infarcts were classified as watershed or embolic using prespecified criteria. RESULTS: Acute infarct on magnetic resonance imaging was seen in 79 of 129 patients (61%), and interrater reliability for stroke pathogenesis was high (κ=0.93). Embolic infarcts only were identified in 60 patients (46%), watershed only in 2 (2%), and both in 17 (13%). In multivariable logistic regression, embolic infarct was associated with aortic arch atheroma (odds ratio [OR], 3.4; 95% confidence interval [CI], 1.0-12.0; P=0.055), old subcortical infarcts (OR, 5.5; 95% CI, 1.1-26.6; P=0.04), no history of percutaneous transluminal coronary angioplasty or coronary artery bypass graft (OR, 4.0; 95% CI, 1.2-13.7; P=0.03), and higher aortic valve gradient (OR, 1.3 per 5 mm Hg; 95% CI, 1.09-1.6; P=0.004). Watershed infarct was associated with internal carotid artery stenosis ≥70% (OR, 11.7; 95% CI, 1.8-76.8; P=0.01) and increased left ventricular ejection fraction (OR, 1.6 per 5% increase; 95% CI, 1.08-2.4; P=0.02). CONCLUSIONS: The principal mechanism of acute cerebral infarction after aortic valve replacement is embolism. There are distinct factors associated with watershed and embolic infarct, some of which may be modifiable.

Lipoprotein-Associated Phospholipase A2 Activity Is a Marker of Risk But Not a Useful Target for Treatment in Patients With Stable Coronary Heart Disease.

BACKGROUND: We evaluated lipoprotein-associated phospholipase A2 (Lp-PLA2) activity in patients with stable coronary heart disease before and during treatment with darapladib, a selective Lp-PLA2 inhibitor, in relation to outcomes and the effects of darapladib in the STABILITY trial. METHODS AND RESULTS: Plasma Lp-PLA2 activity was determined at baseline (n=14 500); at 1 month (n=13 709); serially (n=100) at 3, 6, and 18 months; and at the end of treatment. Adjusted Cox regression models evaluated associations between Lp-PLA2 activity levels and outcomes. At baseline, the median Lp-PLA2 level was 172.4 µmol/min per liter (interquartile range 143.1-204.2 µmol/min per liter). Comparing the highest and lowest Lp-PLA2 quartile groups, the hazard ratios were 1.50 (95% CI 1.23-1.82) for the primary composite end point (cardiovascular death, myocardial infarction, or stroke), 1.95 (95% CI 1.29-2.93) for hospitalization for heart failure, 1.42 (1.07-1.89) for cardiovascular death, and 1.37 (1.03-1.81) for myocardial infarction after adjustment for baseline characteristics, standard laboratory variables, and other prognostic biomarkers. Treatment with darapladib led to a ≈65% persistent reduction in median Lp-PLA2 activity. There were no associations between on-treatment Lp-PLA2 activity or changes of Lp-PLA2 activity and outcomes, and there were no significant interactions between baseline and on-treatment Lp-PLA2 activity or changes in Lp-PLA2 activity levels and the effects of darapladib on outcomes. CONCLUSIONS: Although high Lp-PLA2 activity was associated with increased risk of cardiovascular events, pharmacological lowering of Lp-PLA2 activity by ≈65% did not significantly reduce cardiovascular events in patients with stable coronary heart disease, regardless of the baseline level or the magnitude of change of Lp-PLA2 activity. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00799903.

Ankle Brachial Index and Subsequent Cardiovascular Disease Risk in Patients With Chronic Kidney Disease.

BACKGROUND: The clinical implications of ankle-brachial index (ABI) cutpoints are not well defined in patients with chronic kidney disease (CKD) despite increased prevalence of high ABI attributed to arterial stiffness. We examined the relationship of ABI with cardiovascular disease (CVD) and all-cause mortality among CKD patients. METHODS AND RESULTS: Three thousand six hundred twenty-seven participants without clinical peripheral artery disease (PAD) at baseline from the Chronic Renal Insufficiency Cohort Study were included. ABI was obtained per standard protocol and CVD events were confirmed by medical record adjudication. A U-shaped association of ABI with PAD, myocardial infarction (MI), composite CVD, and all-cause mortality was observed. Individuals with an ABI between 1.0 and <1.4 had the lowest risk of outcomes. Compared to participants with an ABI between 1.0 and <1.4, multiple-adjusted hazard ratios (95% confidence intervals) for those with an ABI of <0.9, 0.9 to <1.0, and ≥1.4 were 5.78 (3.57, 9.35), 2.76 (1.56, 4.88), and 4.85 (2.05, 11.50) for PAD; 1.67 (1.23, 2.29), 1.85 (1.33, 2.57), and 2.08 (1.10, 3.93) for MI; 1.51 (1.27, 1.79), 1.39 (1.15, 1.68), and 1.23 (0.82, 1.84) for composite CVD; and 1.55 (1.28, 1.89), 1.36 (1.10, 1.69), and 1.00 (0.62, 1.62) for all-cause mortality, respectively. CONCLUSIONS: This study indicates that ABI <1.0 was related to risk of PAD, MI, composite CVD, and all-cause mortality whereas ABI ≥1.4 was related to clinical PAD. These findings suggest that ABI cutpoints of <1.0 or ≥1.4 for diagnosing PAD and ABI <1.0 for CVD risk stratification should be further evaluated among CKD patients.

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.