Skeletal Muscle Perfusion Research Articles

Leg Blood Flow and Fatigability In People With Type 2 Diabetes

We have previously demonstrated that people with type 2 diabetes mellitus (T2D) have greater fatigability of the knee extensor muscles during a dynamic fatiguing contraction due to impairments within the skeletal muscle; however, the precise mechanism(s) are unknown. PURPOSE: To determine if impairments in leg blood flow are associated with greater fatigability of the knee extensor muscles during a dynamic fatiguing contraction in men and women with T2D. METHODS: 5 individuals with non-insulin dependent T2D (60 - 70 years; 3 women) with no signs of diabetic neuropathy were matched based on age, BMI and physical activity with four non-diabetic controls (CON) (60 - 68 years; 2 women). Physical activity was assessed over four days with a tri-axial accelerometer. To assess fatigability, participants performed a 6-minute single-limb dynamic fatiguing contractions with the knee extensors while seated at 90° of hip and knee flexion. 120 maximal voluntary concentric contractions (MVCCs) were performed with a load equivalent to 20% maximal voluntary isometric contraction torque through a 90° range of motion. Doppler ultrasonograpy was used to assess femoral artery diameter and pulse wave blood velocity before and immediately after the dynamic fatiguing contraction. RESULTS: The reduction in MVCC power was greater for T2D (40.5 ± 17.6%) compared with CON (31.3 ± 20.8%, P < 0.05) as assessed at the end of exercise. T2D and CON both demonstrated similar increases in leg blood flow after the dynamic fatiguing contraction (71.7 ± 41.1% vs. 69.0 ± 37.3%, respectively; p > 0.05). However, greater reductions in MVCC power (i.e. greater fatigability) was associated with lower blood flow following dynamic fatiguing contractions (p = 0.034, r = 0.633). CONCLUSIONS: Greater fatigability of the knee extensor muscles during dynamic fatiguing contractions was associated with lower blood flow. Impaired blood flow responses to exercise may limit exercise performance among T2D, and this work highlights the need for future studies that examine skeletal muscle perfusion during dynamic exercise in people with T2D. Supported by Marquette University Way Klingler Research Fellowship to SKH

Altered Distribution of Adrenergic Constrictor Responses Contributes to Skeletal Muscle Perfusion Abnormalities in Metabolic Syndrome

Although studies have suggested elevations in adrenergic traffic, signaling and vascular responses with development of metabolic syndrome in obese Zucker rats (OZR), the moderate hypertension and modest impact on organ blood flow in OZR questions the multi‐scale validity of these data. To better understand the role of adrenergic function in contributing to vascular reactivity in OZR, we utilized a multi‐scale approach to investigate pressure responses, skeletal muscle blood flow and vascular reactivity in OZR following adrenergic challenge. For OZR under in vivo conditions, adrenergic challenge resulted increased pressor responses vs. LZR that were mediated via α1 receptors, with minimal contribution by either ROS or NO bioavailability. In situ gastrocnemius muscle of OZR exhibited blunted hyperemic responses to elevated metabolic demand, partially restored with α1 inhibition, although improved muscle performance and VO2 required combined treatment with TEMPOL as well. Within in situ cremaster muscle, proximal resistance arterioles of OZR exhibited a more heterogeneous constrictor response to adrenergic challenge, biased toward hyperresponsiveness, as compared to that in LZR. This increasingly heterogeneous pattern was mirrored in ex vivo resistance arterioles as well, mediated via α1 receptors, with roles for ROS and NO bioavailability evident in hyperresponsive vessels only. These results support observations of the central role of the α1 adrenoreceptor for augmented pressor responses and elevations in vascular resistance, but identify an increased heterogeneity of constrictor reactivity with development of metabolic syndrome that is presently of unclear purpose.Support or Funding InformationNational Institutes of Health and American Heart Association

Systemic application of carbon monoxide-releasing molecule 3 protects skeletal muscle from ischemia-reperfusion injury

ObjectiveIschemia-reperfusion (IR) is a limb- and life-threatening complication of acute limb ischemia and musculoskeletal trauma. Carbon monoxide-releasing molecules (CORMs) have recently been shown to protect microvascular perfusion and to reduce inflammation and injury in various ischemic animal models. The purpose of this study was to examine the effects of water-soluble CORM-3 on the extent of IR-induced muscle injury. MethodsWistar rats were randomized into three groups: sham (no ischemia), IR + CORM-3 (10 mg/kg intraperitoneally), and IR + inactive CORM-3 (iCORM-3; 10 mg/kg intraperitoneally). No-flow ischemia was induced by the application of a tourniquet to the hind limb for 2 hours; tourniquet release commenced the reperfusion phase. Both CORM-3 and iCORM-3 were injected immediately after tourniquet release. Temporal changes in microvascular perfusion, cellular tissue injury (ethidium bromide and bisbenzimide staining), and inflammatory response (leukocyte recruitment) within the extensor digitorum longus muscle were assessed using intravital video microscopy every 15 minutes for a total of 90 minutes after initiation of reperfusion. Systemic levels of tumor necrosis factor-α were also measured. ResultsHind limb IR resulted in (1) a significant no-reflow phenomenon followed by progressive increase in microvascular perfusion deficit (21% ± 2% continuously perfused capillaries in IR vs 76% ± 4% in sham [P < .001]; 52% ± 8% nonperfused capillaries in IR vs 13% ± 2% in sham at 90 minutes of reperfusion [P < .001]), (2) tissue injury (ethidium bromide and bisbenzimide staining of 0.52 ± 0.07 in IR vs 0.05 ± 0.03 in sham at 90 minutes of reperfusion [P < .001]), (3) leukocyte recruitment (13.7 ± 0.9 adherent leukocytes/30 seconds/1000 μm2 in IR vs 1.8 ± 0.5 adherent leukocytes/30 seconds/1000 μm2 in sham at 90 minutes of reperfusion [P < .001]), and (4) an increase in circulating tumor necrosis factor-α levels. Systemic administration of CORM-3 (but not of iCORM-3) effectively reduced the IR-associated skeletal muscle perfusion deficits, tissue injury, and inflammatory activation. ConclusionsCORM-3 displays potent protective and anti-inflammatory effects in an experimental model of hind limb IR, suggesting a potential therapeutic application of CORMs in treatment of ischemic conditions.

The influence of adipose tissue on spatially resolved near-infrared spectroscopy derived skeletal muscle oxygenation: the extent of the problem

Objective. Near-infrared spectroscopy (NIRS) measurements of tissue oxygen saturation (StO2) are useful for the assessment of skeletal muscle perfusion and function during exercise, however, they are influenced by overlying skin and adipose tissue. This study explored the extent and nature of the influence of adipose tissue thickness (ATT) on StO2. Approach. NIR spatially resolved spectroscopy (SRS) derived oxygenation was measured on vastus lateralis in 56 patients with chronic heart failure (CHF) and 20 healthy control (HC) subjects during rest and moderate intensity exercise with simultaneous assessment of oxygen uptake kinetics (τ). In vitro measurements were performed on a flow cell with a blood mixture with full oxygen saturation (100%), which was gradually decreased to 0% by adding sodium metabisulfite. Experiments were repeated with 2 mm increments of porcine fat layer between the NIRS device and flow cell up to 14 mm. Main results. Lower ATT, higher τ, and CHF were independently associated with lower in vivo StO2 in multiple regression analysis, whereas age and gender showed no independent relationship. With greater ATT, in vitro StO2 was reduced from 100% to 74% for fully oxygenated blood and increased from 0% to 68% for deoxygenated blood. Significance. This study shows that ATT independently confounds NIR-SRS derived StO2 by overestimating actual skeletal muscle oxygenation and by decreasing its sensitivity for deoxygenation. Because physiological properties (e.g. presence of disease and slowing of τ) also influence NIR-SRS, a correction based on optical properties is needed to interpret calculated values as absolute StO2.

Altered distribution of adrenergic constrictor responses contributes to skeletal muscle perfusion abnormalities in metabolic syndrome.

Although studies suggest elevated adrenergic activity paralleling metabolic syndrome in OZRs, the moderate hypertension and modest impact on organ perfusion question the multi-scale validity of these data. To understand how adrenergic function contributes to vascular reactivity in OZR, we utilized a multi-scale approach to investigate pressure responses, skeletal muscle blood flow, and vascular reactivity following adrenergic challenge. For OZR, adrenergic challenge resulted in increased pressor responses vs LZRs, mediated via α1 receptors, with minimal contribution by either ROS or NO bioavailability. In situ gastrocnemius muscle of OZR exhibited blunted functional hyperemia, partially restored with α1 inhibition, although improved muscle performance and VO2 required combined treatment with TEMPOL. Within OZR in situ cremaster muscle, proximal arterioles exhibited a more heterogeneous constriction to adrenergic challenge, biased toward hyperresponsiveness, vs LZR. This increasingly heterogeneous pattern was mirrored in ex vivo arterioles, mediated via α1 receptors, with roles for ROS and NO bioavailability evident in hyperresponsive vessels only. These results support the central role of the α1 adrenoreceptor for augmented pressor responses and elevations in vascular resistance, but identify an increased heterogeneity of constrictor reactivity in OZR that is presently of unclear purpose.

Impaired Tissue Oxygenation in Metabolic Syndrome Requires Increased Microvascular Perfusion Heterogeneity.

Metabolic syndrome (MS) in obese Zucker rats (OZR) is associated with impaired skeletal muscle performance and blunted hyperemia. Studies suggest that reduced O2 diffusion capacity is required to explain compromised muscle performance and that heterogeneous microvascular perfusion distribution is critical. We modeled tissue oxygenation during muscle contraction in control and OZR skeletal muscle using physiologically realistic relationships. Using a network model of Krogh cylinders with increasing perfusion asymmetry and increased plasma skimming, we predict increased perfusion heterogeneity and decreased muscle oxygenation in OZR, with partial recovery following therapy. Notably, increasing O2 delivery had less impact on VO2 than equivalent decreases in O2 delivery, providing a mechanism for previous empirical work associating perfusion heterogeneity and impaired O2 extraction. We demonstrate that increased skeletal muscle perfusion asymmetry is a defining characteristic of MS and must be considered to effectively model and understand blood-tissue O2 exchange in this model of human disease.

Role of Insulin-Stimulated Adipose Tissue Perfusion in the Development of Whole-Body Insulin Resistance.

An online visual overview is available for this article.

Regulation of microvascular flow and metabolism: An overview.

Skeletal muscle is an important site for insulin to regulate blood glucose levels. It is estimated that skeletal muscle is responsible for ~80% of insulin-mediated glucose disposal in the post-prandial period. The classical action of insulin to increase muscle glucose uptake involves insulin binding to insulin receptors on myocytes to stimulate glucose transporter 4 (GLUT 4) translocation to the cell surface membrane, enhancing glucose uptake. However, an additional role of insulin that is often under-appreciated is its action to increase muscle perfusion thereby improving insulin and glucose delivery to myocytes. Either of these responses (myocyte and/or vascular) may be impaired in insulin resistance, and both impairments are apparent in type 2 diabetes, resulting in diminished glucose disposal by muscle. The aim of this review is to report on the growing body of literature suggesting that insulin-mediated control of skeletal muscle perfusion is an important regulator of muscle glucose uptake and that impairment of microvascular insulin action has important physiological consequences early in the pathogenesis of insulin resistance. This work was discussed at the 2015 Australian Physiological Society Symposium "Physiological mechanisms controlling microvascular flow and muscle metabolism".

Higher Myocardial and Skeletal Muscle Microvascular Flow in Sickle Cell Disease Patients on Hydroxyurea

Individuals with SCD have recurrent episodes of ischemia-reperfusion in vital organs, and abnormal microcirculation is considered a major determinant of end organ damage. Hydroxyurea (HU) treatment has been shown to produce ATP- and nitric oxide-mediated vasodilation, and to improve red cells deformability Few tools are available to quantitatively measure microvascular blood flow in vivo. The purpose of this study was to assess the ability of a novel ECHO based imaging modality to assess the effect of hydroxyurea on cardiac and skeletal muscle perfusion in patients with sickle cell anemia.Methods and Results: Twenty-one HBSS/B0 patients, of whom 15 were treated with HU(average daily dose of 18 ± 8 mg/kg/day), underwent brachial artery ultrasound, echocardiography and contrast enhanced ultrasound (CEU) perfusion imaging of deep flexor muscles of the forearm as well as the myocardium at rest and during vasodilator stress with regadenoson ( ClinicalTrials.gov NCT016028090). Quantitative image analysis was performed to obtain microvascular blood volume and flow velocity measurements. Patients on HU had a lower white blood cell count (6.7±2.1 K/uL vs 10.0±2.1 K/uL, p<0.05), higher mean corpuscular volume (103.6±11.5 fL vs 82.5±8.6 fL, p<0.05) , and lower reticulocyte count (9.3±3.4% vs 15.7±5.6%, p<0.05) as well as a trend towards higher hemoglobin (9.4±1.4g/dL vs 7.9±1.1g/dL , p=NS). Table 1. Cardiac output and total myocardial work was not affected by HU treatment and macrovascular flow in the brachial artery was not affected (Figure 1A). In contrast, both skeletal muscle microvascular flow and myocardial microvascular flow was significantly higher in the SCD patients on HU therapy (Figure 1B, 1C).Conclusions: The beneficial effects of HU therapy in SCD are varied, and clinical effects are often seen prior to a rise in fetal hemoglobin. Other effects, such as lower hemolysis, improved red cell deformability, and inhibition of adhesive properties in the microvasculature have been reported. Some of the beneficial effects of HU may be due to stimulation of nitric oxide synthase, induction of cyclic GMP dependent signaling and improved NO bioavailability. Our study indicates that SCD patients on chronic HU therapy have higher levels of myocardial and skeletal muscle microvascular blood flow. Long term studies are necessary to evaluate whether HU reduces end organ damage in SCA.Skeletal muscle and myocardial microvascular blood flow.Each panel shows blood flow in all SCD patients (red filled diamonds), SCD patients not on HU (red open triangles) and SCD patients on HU (red open inverted triangles).Panel A. Skeletal muscle perfusion normalized to hemoglobin (A x β x hemoglobin)Panel B. Myocardial perfusion normalized to hemoglobin level and total myocardial work. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Perfusion has no effect on the in vivo CEST effect from Cr (CrCEST) in skeletal muscle.

Creatine, a key component of muscle energy metabolism, exhibits a chemical exchange saturation transfer (CEST) effect between its amine group and bulk water, which has been exploited to spatially and temporally map creatine changes in skeletal muscle before and after exercise. In addition, exercise leads to an increase in muscle perfusion. In this work, we determined the effects of perfused blood on the CEST effects from creatine in skeletal muscle. Experiments were performed on healthy human subjects (n=5) on a whole-body Siemens 7T magnetic resonance imaging (MRI) scanner with a 28-channel radiofrequency (RF) coil. Reactive hyperemia, induced by inflation and subsequent deflation of a pressure cuff secured around the thigh, was used to increase tissue perfusion whilst maintaining the levels of creatine kinase metabolites. CEST, arterial spin labeling (ASL) and 31 P MRS data were acquired at baseline and for 6min after cuff deflation. Reactive hyperemia resulted in substantial increases in perfusion in human skeletal muscle of the lower leg as measured by the ASL mean percentage difference. However, no significant changes in CrCEST asymmetry (CrCESTasym ) or 31 P MRS-derived PCr levels of skeletal muscle were observed following cuff deflation. This work demonstrates that perfusion changes do not have a major confounding effect on CrCEST measurements.

The Relevance of Sex Differences in Performance Fatigability.

Performance fatigability differs between men and women for a range of fatiguing tasks. Women are usually less fatigable than men, and this is most widely described for isometric fatiguing contractions and some dynamic tasks. The sex difference in fatigability is specific to the task demands so that one mechanism is not universal, including any sex differences in skeletal muscle physiology, muscle perfusion, and voluntary activation. However, there are substantial knowledge gaps about the task dependency of the sex differences in fatigability, the involved mechanisms, and the relevance to clinical populations and with advanced age. The knowledge gaps are in part due to the significant deficits in the number of women included in performance fatigability studies despite a gradual increase in the inclusion of women for the last 20 yr. Therefore, this review 1) provides a rationale for the limited knowledge about sex differences in performance fatigability, 2) summarizes the current knowledge on sex differences in fatigability and the potential mechanisms across a range of tasks, 3) highlights emerging areas of opportunity in clinical populations, and 4) suggests strategies to close the knowledge gap and understanding the relevance of sex differences in performance fatigability. The limited understanding about sex differences in fatigability in healthy and clinical populations presents as a field ripe with opportunity for high-impact studies. Such studies will inform on the limitations of men and women during athletic endeavors, ergonomic tasks, and daily activities. Because fatigability is required for effective neuromuscular adaptation, sex differences in fatigability studies will also inform on optimal strategies for training and rehabilitation in both men and women.

Supplementing essential amino acids with the nitric oxide precursor, l-arginine, enhances skeletal muscle perfusion without impacting anabolism in older men.

Postprandial limb blood flow and skeletal muscle microvascular perfusion reduce with aging. Here we tested the impact of providing bolus essential amino acids (EAA) in the presence and absence of the nitric oxide precursor, l-Arginine (ARG), upon skeletal muscle blood flow and anabolism in older men. Healthy young (YOUNG: 19.7±0.5y, N=8) and older men (OLD, 70±0.8y, N=8) received 15g EAA or (older only) 15g EAA +3g ARG (OLD-ARG, 69.2±1.2y, N=8). We quantified responses in muscle protein synthesis (MPS; incorporation of 13C phenylalanine into myofibrillar proteins), leg and muscle microvascular blood flow (Doppler/contrast enhanced ultrasound (CEUS)) and insulin/EAA in response to EEA±ARG. Plasma EAA increased similarly across groups but argininemia was evident solely in OLD-ARG (∼320mmol, 65min post feed); increases in plasma insulin (to ∼13IUml-1) were similar across groups. Increases in femoral flow were evident in YOUNG >2h after feeding; these effects were blunted in OLD and OLD-ARG. Increases in microvascular blood volume (MBV) occurred only in YOUNG and these effects were isolated to the early postprandial phase (+45% at ∼45min after feeding) coinciding with detectable arterio-venous differences in EAA reflecting net uptake by muscle. Increases in microvascular flow velocity (MFV) and tissue perfusion (MBV×MFV) occurred (∼2h) in YOUNG and OLD-ARG, but not OLD. Postprandial protein accretion was greater in YOUNG than OLD or OLD-ARG; the latter two groups being indistinguishable. Therefore, ARG rescues aspects of muscle perfusion in OLD without impacting anabolic blunting, perhaps due to the "rescue" being beyond the period of active EAA-uptake.

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

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. 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). 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. 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.

Skeletal myofiber VEGF regulates contraction-induced perfusion and exercise capacity but not muscle capillarity in adult mice.

A single bout of exhaustive exercise signals expression of vascular endothelial growth factor (VEGF) in the exercising muscle. Previous studies have reported that mice with life-long deletion of skeletal myofiber VEGF have fewer capillaries and a severe reduction in endurance exercise. However, in adult mice, VEGF gene deletion conditionally targeted to skeletal myofibers limits exercise capacity without evidence of capillary regression. To explain this, we hypothesized that adult skeletal myofiber VEGF acutely regulates skeletal muscle perfusion during muscle contraction. A tamoxifen-inducible skeletal myofiber-specific VEGF gene deletion mouse (skmVEGF-/-) was used to reduce skeletal muscle VEGF protein by 90% in adult mice. Three weeks after inducing deletion of the skeletal myofiber VEGF gene, skmVEGF-/- mice exhibited diminished maximum running speed (-10%, P < 0.05) and endurance capacity (-47%; P < 0.05), which did not persist after 8 wk. In skmVEGF-/- mice, gastrocnemius complex time to fatigue measured in situ was 71% lower than control mice. Contraction-induced perfusion measured by optical imaging during a period of electrically stimulated muscle contraction was 85% lower in skmVEGF-/- than control mice. No evidence of capillary rarefication was detected in the soleus, gastrocnemius, and extensor digitorum longus (EDL) up to 8 wk after tamoxifen-induced VEGF ablation, and contractility and fatigue resistance of the soleus measured ex vivo were also unchanged. The force-frequency of the EDL showed a small right shift, but fatigue resistance did not differ between EDL from control and skmVEGF-/- mice. These data suggest myofiber VEGF is required for regulating perfusion during periods of contraction and may in this manner affect endurance capacity.

Synchronizing Foot Strike and Cardiac Cycle Phase Affects Heart Rate and Metabolic Responses to Running

The interplay between physiological factors such as muscle perfusion and venous return to the heart has a major role in cardiovascular and peripheral responses during running. Timing cardiac contraction (i.e. systole) to occur in synchrony with skeletal muscle relaxation (swing phase of the gait cycle) may reduce cardiac afterload and promote coronary and skeletal muscle perfusion. In turn, this should manifest in a reduced HR response at a constant running velocity, secondary to an increased stroke volume. PURPOSE: To assess HR and metabolic responses associated with running when foot strikes are timed to occur during 1) the systolic phase of the cardiac cycle, or 2) the diastolic phase. METHODS: Ten elite male distance runners performed a testing session on the treadmill at 4.72 m/s (5:40 min/mile) pace while matching their steps to an auditory tone and wearing a chest strap that generated accelerometer and ECG signals. Testing began with a 3-min control stage (no tone), immediately followed by 2 or 3 pairs of “toned” stepping phases (pair = 2 x 3-min), where the signal to step was given either at 100% of the subject’s R-R interval (systolic stepping; SS) or 45% of R-R (diastolic stepping; DS). The order of DS and SS within each pair was randomized and double blinded. VO2, VE and RER were measured continuously. RESULTS: Twenty-eight pairs of DS + SS were used for HR, step rate (SR) and length (SL) comparisons and 24 pairs were included in metabolic data analyses. All subjects accurately timed their steps with the auditory tones (DS: 45.0 ± 4.3 %; SS: 100.1 ± 5.0 % of R-R interval). While VO2 was similar, HR, SR, VE and RER were significantly (p < 0.001) lower during DS compared to SS (HR: 172 ± 6 vs 175 ± 7 beats·min-1; SR: 172 ± 6 vs 175 ± 7 steps·min-1; VE: 100.0 ± 10.8 vs 103.7 ± 11.8 l·min-1; RER: 0.93 ± 0.03 vs 0.95 ± 0.03, for DS & SS, respectively) despite subjects having to lengthen their steps more during DS compared to SS (p < 0.001; 2.5 ± 3.1 vs 0.9 ± 3.2 % of control SL, respectively) to match HR. CONCLUSION: Synchronizing foot strike to occur during diastole, as opposed to systole, reduces HR during running, presumably as a result of an increase in stroke volume and/or enhanced muscle perfusion. The cardiac advantage with DS may be beneficial to distance running performance. Supported by a grant from Pulson Inc.

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).

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. 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. 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). 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.

The Influence of Subsystolic Occlusion on Cardiac Power during Submaximal Locomotor Exercise in Healthy Aging Adults

IntroductionHealthy aging in adults is associated with attenuated cardiac output (Q) for a given exercise workload compared to younger healthy adults. This is important because skeletal muscle perfusion pressure during exercise is dependent on coordinated adjustments between cardiac and vascular hemodynamics. Cardiac power (CP) quantifies the flow and peripheral pressure generating capacity of the heart, and may be the strongest measure of cardiac function during exercise. Group III/IV muscle afferents are suggested to favorably influence Q and arterial pressure during exercise in young healthy adults. However, the influence of group III/IV afferents on cardiac hemodynamic and arterial pressure coupling during exercise remains unclear across the aging spectrum. Venous distension via subsystolic circulatory occlusion of locomotor muscles is suggested to increase group III/IV afferent outflow. The aim of this study was to assess the influence of subsystolic circulatory occlusion of locomotor muscles on CP in young vs aging healthy adults.MethodsHealthy adults completed 2 visits (10 young [YNG] vs 9 OLD; age 22±1 vs 66±3 yrs, BSA 1.8±0.1 vs 1.9±0.1 m2; % predicted peak VO2 99±7 vs 115±7 %; peak workload 188±16 vs 144±9 W, respectively; age and workload P&lt;0.05). Visit 1: peak exercise test. Visit 2: constant load cycle ergometry at 30% peak workload (YNG=56±5 vs OLD=43±3 W, P&lt;0.05) with the first 3 min without cuffing (0 mm Hg), but thereafter included intermittent subsystolic bilateral thigh cuff inflations to 20, 40, 60, 80, or 100 mm Hg for 2 min (randomized), with 2 min deflation between inflations. Non‐invasive Q and mean arterial (MAP) pressure were measured using continuous hemodynamic photoplethysmography. We calculated CP=Q*MAP. Q and CP were indexed to BSA.ResultsAt rest, MAP did not differ in YNG vs OLD, but Q and CP were higher in YNG vs OLD (P&lt;0.05), which persisted throughout each exercise cuff occlusion. In YNG, the greatest increase in CP from 0 mm Hg occurred at 100 mm Hg (754±48 vs 899±48 L/min/m2 · mm Hg, P&lt;0.05) due to increased MAP (19±4%, P&lt;0.05) but not Q (1±2%, P&gt;0.05). In OLD, Q, MAP, and CP did not differ between 0 mm Hg and any occlusion (P&gt;0.05). The % increase in Q from rest to 0, 20, 60, 80, and 100 mm Hg was higher in YNG vs OLD (P&lt;0.05). The % increase in MAP from rest to any occlusion did not differ in YNG vs OLD (P&gt;0.05). The % increase in CP from rest to occlusions of 60 (130±9 vs 98±11%), 80 (142±9 vs 108±20%), and 100 (158±11 vs 114±14%) were higher in YNG vs OLD (all P&lt;0.05). Within YNG, the % increase in CP from rest to 100 mm Hg was higher than the % increase from rest to 0, 20, 40, or 60 mm Hg (P&lt;0.05), driven by increased MAP (P&lt;0.05). Within OLD, these differences for % increase in CP did not occur despite MAP that was similar to YNG (P&gt;0.05).ConclusionsThese data suggest that CP is attenuated in OLD vs YNG healthy adults during subsystolic circulatory occlusion of locomotor muscles during submaximal constant load exercise. The reduced CP generation in older adults is related to a blunted increase in Q mediated by attenuated influence of group III/IV muscle afferents on cardiac function during exercise.

Calf muscle perfusion as measured with magnetic resonance imaging to assess peripheral arterial disease.

We hypothesized that skeletal muscle perfusion is impaired in peripheral arterial disease (PAD) patients compared to healthy controls and that perfusion patterns exhibit marked differences across five leg muscle compartments including the anterior muscle group (AM), lateral muscle group (LM), deep posterior muscle group (DM), soleus (SM), and the gastrocnemius muscle (GM). A total of 40 individuals (26 PAD patients and 14 healthy controls) underwent contrast-enhanced magnetic resonance imaging (CE-MRI) utilizing a reactive hyperemia protocol. Muscle perfusion maps were developed for AM, LM, DM, SM, and GM. Perfusion maps were analyzed over the course of 2min, starting at local pre-contrast arrival, to study early-to-intermediate gadolinium enhancement. PAD patients had a higher fraction of hypointense voxels at pre-contrast arrival for all five muscle compartments compared with healthy controls (p<0.0005). Among PAD patients, the fraction of hypointense voxels of the AM, LM, and GM were inversely correlated with the estimated glomerular filtration rate (eGFR; r=-0.509, p=0.008; r=-0.441, p=0.024; and r=-0.431, p=0.028, respectively). CE-MRI-based skeletal leg muscle perfusion is markedly reduced in PAD patients compared with healthy controls and shows heterogeneous patterns across calf muscle compartments.

Acute cocoa flavanol supplementation improves muscle macro- and microvascular but not anabolic responses to amino acids in older men.

The anabolic effects of nutrition on skeletal muscle may depend on adequate skeletal muscle perfusion, which is impaired in older people. Cocoa flavanols have been shown to improve flow-mediated dilation, an established measure of endothelial function. However, their effect on muscle microvascular blood flow is currently unknown. Therefore, the objective of this study was to explore links between the consumption of cocoa flavanols, muscle microvascular blood flow, and muscle protein synthesis (MPS) in response to nutrition in older men. To achieve this objective, leg blood flow (LBF), muscle microvascular blood volume (MBV), and MPS were measured under postabsorptive and postprandial (intravenous Glamin (Fresenius Kabi, Germany), dextrose to sustain glucose ∼7.5 mmol·L(-1)) conditions in 20 older men. Ten of these men were studied with no cocoa flavanol intervention and a further 10 were studied with the addition of 350 mg of cocoa flavanols at the same time that nutrition began. Leg (femoral artery) blood flow was measured by Doppler ultrasound, muscle MBV by contrast-enhanced ultrasound using Definity (Lantheus Medical Imaging, Mass., USA) perflutren contrast agent and MPS using [1, 2-(13)C2]leucine tracer techniques. Our results show that although older individuals do not show an increase in LBF or MBV in response to feeding, these absent responses are apparent when cocoa flavanols are given acutely with nutrition. However, this restoration in vascular responsiveness is not associated with improved MPS responses to nutrition. We conclude that acute cocoa flavanol supplementation improves muscle macro- and microvascular responses to nutrition, independently of modifying muscle protein anabolism.

Heart Failure Impairs Muscle Blood Flow and Endurance Exercise Tolerance in COPD

Heart failure, a prevalent and disabling co-morbidity of COPD, may impair cardiac output and muscle blood flow thereby contributing to exercise intolerance. To investigate the role of impaired central and peripheral hemodynamics in limiting exercise tolerance in COPD-heart failure overlap, cycle ergometer exercise tests at 20% and 80% peak work rate were performed by overlap (FEV1 = 56.9 ± 15.9% predicted, ejection fraction = 32.5 ± 6.9%; N = 16), FEV1-matched COPD (N = 16), ejection fraction-matched heart failure patients (N = 15) and controls (N = 12). Differences (Δ) in cardiac output (impedance cardiography) and vastus lateralis blood flow (indocyanine green) and deoxygenation (near-infrared spectroscopy) between work rates were expressed relative to concurrent changes in muscle metabolic demands (ΔO2 uptake). Overlap patients had approximately 30% lower endurance exercise tolerance than COPD and heart failure (p < 0.05). ΔBlood flow was closely proportional to Δcardiac output in all groups (r = 0.89–0.98; p < 0.01). Overlap showed the largest impairments in Δcardiac output/ΔO2 uptake and Δblood flow/ΔO2 uptake (p < 0.05). Systemic arterial oxygenation, however, was preserved in overlap compared to COPD. Blunted limb perfusion was related to greater muscle deoxygenation and lactate concentration in overlap (r = 0.78 and r = 0.73, respectively; p < 0.05). ΔBlood flow/ΔO2 uptake was related to time to exercise intolerance only in overlap and heart failure (p < 0.01). In conclusion, COPD and heart failure add to decrease exercising cardiac output and skeletal muscle perfusion to a greater extent than that expected by heart failure alone. Treatment strategies that increase muscle O2 delivery and/or decrease O2 demand may be particularly helpful to improve exercise tolerance in COPD patients presenting heart failure as co-morbidity.