Luke J. Haseler

Dynamic imaging of perfusion in human skeletal muscle during exercise with arterial spin labeling

MR images acquired by using an arterial spin‐labeling technique showed spatial and temporal variations of perfusion in the skeletal muscle of exercising humans. Perfusion measurements made during plantar flexion exercise in normal volunteers were consistent with those obtained by traditional techniques reported in the literature. Spatial heterogeneity of perfusion values clearly delineated the various muscle groups within the lower leg. These results are interpreted in terms of a quantitative model for the perfusion signal in muscle. This method can provide a useful tool in the study of muscle physiology. Magn Reson Med 42:258–267, 1999. Published 1999 Wiley‐Liss, Inc.

Adenosine and its receptors in the heart: Regulation, retaliation and adaptation

The purine nucleoside adenosine is an important regulator within the cardiovascular system, and throughout the body. Released in response to perturbations in energy state, among other stimuli, local adenosine interacts with 4 adenosine receptor sub-types on constituent cardiac and vascular cells: A(1), A(2A), A(2B), and A(3)ARs. These G-protein coupled receptors mediate varied responses, from modulation of coronary flow, heart rate and contraction, to cardioprotection, inflammatory regulation, and control of cell growth and tissue remodeling. Research also unveils an increasingly complex interplay between members of the adenosine receptor family, and with other receptor groups. Given generally favorable effects of adenosine receptor activity (e.g. improving the balance between myocardial energy utilization and supply, limiting injury and adverse remodeling, suppressing inflammation), the adenosine receptor system is an attractive target for therapeutic manipulation. Cardiovascular adenosine receptor-based therapies are already in place, and trials of new treatments underway. Although the complex interplay between adenosine receptors and other receptors, and their wide distribution and functions, pose challenges to implementation of site/target specific cardiovascular therapy, the potential of adenosinergic pharmacotherapy can be more fully realized with greater understanding of the roles of adenosine receptors under physiological and pathological conditions. This review addresses some of the major known and proposed actions of adenosine and adenosine receptors in the heart and vessels, focusing on the ability of the adenosine receptor system to regulate cell function, retaliate against injurious stressors, and mediate longer-term adaptive responses.

The role of oxygen in determining phosphocreatine onset kinetics in exercising humans

31P‐magnetic resonance spectroscopy was used to study phosphocreatine (PCr) onset kinetics in exercising human gastrocnemius muscle under varied fractions of inspired O2 (FIO2). Five male subjects performed three identical work bouts (5 min duration; order randomised) at a submaximal workload while breathing 0.1, 0.21 or 1.0 FIO2. Either a single or double exponential model was fitted to the PCr kinetics. The phase I τ (0.1, 38.6 ± 7.5; 0.21, 34.5 ± 7.9; 1.0, 38.6 ± 9.2 s) and amplitude, A1 (0.1, 0.34 ± 0.03; 0.21, 0.28 ± 0.05; 1.0, 0.28 ± 0.03,% fall in PCr) were invariant (both P > 0.05) across FIO2 trials. The initial rate of change in PCr hydrolysis at exercise onset, calculated as A1/τ1 (%PCr reduction s−1), was the same across FIO2 trials. A PCr slow component (phase II) was present at an FIO2 of 0.1 and 0.21; however, breathing 1.0 FIO2 ablated the slow component. The onset of the slow component resulted in a greater (P≤ 0.05) overall percentage fall in PCr (both phase I and II) as FIO2 decreased (0.43 ± 0.05, 0.34 ± 0.05, 0.28 ± 0.03) for 0.1, 0.21 and 1.0 FIO2, respectively. These data demonstrate that altering FIO2 does not affect the initial phase I PCr onset kinetics, which supports the notion that O2 driving pressure does not limit PCr kinetics at the onset of submaximal exercise. Thus, these data imply that the manner in which microvascular and intracellular PO2 regulates PCr hydrolysis in exercising muscle is not due to the initial kinetic fall in PCr at exercise onset.

Does ultrasound guidance improve the outcomes of arthrocentesis and corticosteroid injection of the knee

Objective: The present randomized controlled trial compared arthrocentesis of the effusive knee followed by corticosteroid injection performed by the conventional anatomic landmark palpation-guided technique to the same procedure performed with ultrasound (US) needle guidance. Methods: Sixty-four palpably effusive knees were randomized to (i) palpation-guided arthrocentesis with a conventional 20-mL syringe (22 knees), (ii) US-guided arthrocentesis with a 25-mL reciprocating procedure device (RPD) mechanical aspirating syringe (22 knees), or (iii) US-guided arthrocentesis with a 60-mL automatic aspirating syringe (20 knees). The one-needle two-syringe technique was used. Outcome measures included patient pain by the Visual Analogue Scale (VAS) for pain (0–10 cm), the proportion of diagnostic samples, synovial fluid volume yield, complications, and therapeutic outcome at 2 weeks. Results: Sonographic guidance resulted in 48% less procedural pan (VAS; palpation-guided: 5.8 ± 3.0 cm, US-guided: 3.0 ± 2.8 cm, p < 0.001), 183% increased aspirated synovial fluid volumes (palpation-guided: 12 ± 10 mL, US-guided: 34 ± 25 mL, p < 0.0001), and improved outcomes at 2 weeks (VAS; palpation-guided: 2.8 ± 2.4 cm, US-guided: 1.5 ± 1.9 cm, p = 0.034). Outcomes of sonographic guidance with the mechanical syringe and automatic syringe were comparable in all outcome measures. Conclusions: US-guided arthrocentesis and injection of the knee are superior to anatomic landmark palpation-guided arthrocentesis, resulting in significantly less procedural pain, improved arthrocentesis success, greater synovial fluid yield, more complete joint decompression, and improved clinical outcomes.

Use of Three-Dimensional Speckle-Tracking Echocardiography for Quantitative Assessment of Global Left Ventricular Function: A Comparative Study to Three-Dimensional Echocardiography

BACKGROUND The aim of this study was to determine whether global strains derived from three-dimensional (3D) speckle-tracking echocardiography (STE) are as accurate as left ventricular (LV) ejection fraction (LVEF) obtained by two-dimensional (2D) and 3D echocardiography in the quantification of LV function. METHODS Two-dimensional and 3D echocardiography and 2D and 3D STE were performed in 88 patients (LVEF range, 17%-79%). Two-dimensional and 3D global longitudinal strain (GLS), global circumferential strain (GCS), global radial strain, and global area strain were quantified and correlated with LV function determined by 2D and 3D echocardiographic LVEF. Reproducibility, feasibility, and duration of study to perform 3D STE were assessed by independent, blinded observers. RESULTS A total of 78 patients (89%) underwent 3D STE. All 3D speckle-tracking echocardiographic parameters had strong correlations with assessment of LV function determined by 2D and 3D echocardiographic LVEF. Three-dimensional GCS was the best marker of LV function (r = -0.89, P < .0001). Subgroup analysis demonstrated that 3D speckle-tracking echocardiographic parameters were particularly useful in identifying LV dysfunction (LVEF < 50%). Receiver operating characteristic curve analysis demonstrated areas under the curve of 0.97 for 3D GCS, 0.96 for 3D global radial strain, 0.95 for 3D global area strain, and 0.87 for 3D GLS. An optimal 3D GCS cutoff value of magnitude < -12% predicted LV dysfunction (LVEF obtained by 2D echocardiography < 50%) with 92% sensitivity and 90% specificity. There was good correlation between 2D GLS and 3D GLS (r = 0.85, P < .001; mean difference, -1.7 ± 6.5%). Good intraobserver, interobserver, and test-retest agreements were seen with 3D STE. Time for image acquisition to postprocessing analysis was significantly reduced with 3D STE (3.7 ± 1.0 minutes) compared with 2D STE (4.6 ± 1.5 min) (P < .05). CONCLUSIONS Global strain by 3D STE is a promising novel alternative to quantitatively assess LV function. Three-dimensional STE is reproducible, feasible, and time efficient.

Transcriptome analysis of neutrophils after endurance exercise reveals novel signaling mechanisms in the immune response to physiological stress

Neutrophils serve as an intriguing model for the study of innate immune cellular activity induced by physiological stress. We measured changes in the transcriptome of circulating neutrophils following an experimental exercise trial (EXTRI) consisting of 1 h of intense cycling immediately followed by 1 h of intense running. Blood samples were taken at baseline, 3 h, 48 h, and 96 h post-EXTRI from eight healthy, endurance-trained, male subjects. RNA was extracted from isolated neutrophils. Differential gene expression was evaluated using Illumina microarrays and validated with quantitative PCR. Gene set enrichment analysis identified enriched molecular signatures chosen from the Molecular Signatures Database. Blood concentrations of muscle damage indexes, neutrophils, interleukin (IL)-6 and IL-10 were increased (P < 0.05) 3 h post-EXTRI. Upregulated groups of functionally related genes 3 h post-EXTRI included gene sets associated with the recognition of tissue damage, the IL-1 receptor, and Toll-like receptor (TLR) pathways (familywise error rate, P value < 0.05). The core enrichment for these pathways included TLRs, low-affinity immunoglobulin receptors, S100 calcium binding protein A12, and negative regulators of innate immunity, e.g., IL-1 receptor antagonist, and IL-1 receptor associated kinase-3. Plasma myoglobin changes correlated with neutrophil TLR4 gene expression (r = 0.74; P < 0.05). Neutrophils had returned to their nonactivated state 48 h post-EXTRI, indicating that their initial proinflammatory response was transient and rapidly counterregulated. This study provides novel insight into the signaling mechanisms underlying the neutrophil responses to endurance exercise, suggesting that their transcriptional activity was particularly induced by damage-associated molecule patterns, hypothetically originating from the leakage of muscle components into the circulation.

Evidence that a higher ATP cost of muscular contraction contributes to the lower mechanical efficiency associated with COPD: preliminary findings

Impaired metabolism in peripheral skeletal muscles potentially contributes to exercise intolerance in chronic obstructive pulmonary disease (COPD). We used (31)P-magnetic resonance spectroscopy ((31)P-MRS) to examine the energy cost and skeletal muscle energetics in six patients with COPD during dynamic plantar flexion exercise compared with six well-matched healthy control subjects. Patients with COPD displayed a higher energy cost of muscle contraction compared with the controls (control: 6.1 ± 3.1% of rest·min(-1)·W(-1), COPD: 13.6 ± 8.3% of rest·min(-1)·W(-1), P = 0.01). Although, the initial phosphocreatine resynthesis rate was also significantly attenuated in patients with COPD compared with controls (control: 74 ± 17% of rest/min, COPD: 52 ± 13% of rest/min, P = 0.04), when scaled to power output, oxidative ATP synthesis was similar between groups (6.5 ± 2.3% of rest·min(-1)·W(-1) in control and 7.8 ± 3.9% of rest·min(-1)·W(-1) in COPD, P = 0.52). Therefore, our results reveal, for the first time that in a small subset of patients with COPD a higher ATP cost of muscle contraction may substantially contribute to the lower mechanical efficiency previously reported in this population. In addition, it appears that some patients with COPD have preserved mitochondrial function and normal energy supply in lower limb skeletal muscle.

Reproducibility of Regional and Global Longitudinal Strains Derived from Two-Dimensional Speckle-Tracking and Doppler Tissue Imaging between Expert and Novice Readers during Quantitative Dobutamine Stress Echocardiography

BACKGROUND Longitudinal strain (LS) is a quantitative parameter that adds incremental value to wall motion analysis. The aim of this study was to compare the reproducibility of LS derived from Doppler tissue imaging and speckle-tracking between an expert and a novice strain reader during dobutamine stress echocardiography (DSE). METHODS Forty-one patients (mean age, 65 ± 15 years; mean ejection fraction, 58 ± 11%) underwent DSE per clinical protocol. Global LS derived from speckle-tracking and regional LS derived from both speckle-tracking and Doppler tissue imaging were measured twice by an expert strain reader and also measured twice by a novice strain reader. Intraobserver and interobserver analyses were performed using intraclass correlation coefficients (ICC), Bland-Altman analysis, and absolute difference values (mean ± SD). RESULTS Global LS measured by the expert strain reader demonstrated high intraobserver measurement reproducibility (rest: ICC = 0.95, absolute difference = 5.5 ± 4.9%; low dose: ICC = 0.96, absolute difference = 5.7 ± 3.7%; peak dose: ICC = 0.87, absolute difference = 11.4 ± 8.4%). Global LS measured by the novice strain reader also demonstrated high intraobserver reproducibility (rest: ICC = 0.97, absolute difference = 4.1 ± 3.4%; low dose: ICC = 0.94, absolute difference = 5.4 ± 5.9%; peak dose: ICC = 0.94, absolute difference = 6.1 ± 4.8%). Global LS also showed high interobserver agreement between the expert and novice readers at all stages of DSE (rest: ICC = 0.90, absolute difference = 8.5 ± 7.5%; low dose: ICC = 0.90, absolute difference = 8.9 ± 7.1%; peak dose: ICC = 0.87, absolute difference = 10.8 ± 8.4%). Of all parameters studied, LS derived from Doppler tissue imaging had relatively low interobserver and intraobserver agreement. CONCLUSIONS Global LS is highly reproducible during all stages of DSE. This variable is a potentially reliable and reproducible measure of myocardial deformation.

Time course-dependent changes in the transcriptome of human skeletal muscle during recovery from endurance exercise: from inflammation to adaptive remodeling

Reprogramming of gene expression is fundamental for skeletal muscle adaptations in response to endurance exercise. This study investigated the time course-dependent changes in the muscular transcriptome after an endurance exercise trial consisting of 1 h of intense cycling immediately followed by 1 h of intense running. Skeletal muscle samples were taken at baseline, 3 h, 48 h, and 96 h postexercise from eight healthy, endurance-trained men. RNA was extracted from muscle. Differential gene expression was evaluated using Illumina microarrays and validated with qPCR. Gene set enrichment analysis identified enriched molecular signatures chosen from the Molecular Signatures Database. Three hours postexercise, 102 gene sets were upregulated [family wise error rate (FWER), P < 0.05], including groups of genes related with leukocyte migration, immune and chaperone activation, and cyclic AMP responsive element binding protein (CREB) 1 signaling. Forty-eight hours postexercise, among 19 enriched gene sets (FWER, P < 0.05), two gene sets related to actin cytoskeleton remodeling were upregulated. Ninety-six hours postexercise, 83 gene sets were enriched (FWER, P < 0.05), 80 of which were upregulated, including gene groups related to chemokine signaling, cell stress management, and extracellular matrix remodeling. These data provide comprehensive insights into the molecular pathways involved in acute stress, recovery, and adaptive muscular responses to endurance exercise. The novel 96 h postexercise transcriptome indicates substantial transcriptional activity potentially associated with the prolonged presence of leukocytes in the muscles. This suggests that muscular recovery, from a transcriptional perspective, is incomplete 96 h after endurance exercise involving muscle damage.

Preliminary findings in the heart rate variability and haemorheology response to varied frequency and duration of walking in women 65–74 yr with type 2 diabetes

Heart rate variability (HRV) and haemorheology adaptations to 12 wk of varied-dose treadmill walking were investigated in women aged 65-74 yr with type 2 diabetes. Subjects were randomly allocated into two groups where exercise frequency and session duration were manipulated (Group 1: 2 × 60 min·wk(-1) or Group 2: 4 × 30 min·wk(-1)), but intensity and accumulated weekly duration of exercise were consistent between groups (100% gas-exchange threshold; 120 min·wk(-1)). Twelve weeks of exercise training significantly improved peak oxygen uptake, time to exhaustion, and gas-exchange threshold (p < 0.05), independent of exercise group. Exercise training did not significantly change glycaemic control or body mass. Red blood cell (RBC) aggregation and RBC deformability significantly decreased (p < 0.05) for both groups. No change in HRV was observed for Group 1, whereas several key indicators of HRV were significantly improved in Group 2 (p < 0.05). The present study was the first to report decreased RBC aggregation following an exercise-only intervention and that exercise training improved RBC aggregation without a concomitant improvement in glycaemic control. The accumulated weekly exercise duration may be the most important training component for the prescription of exercise in older women with type 2 diabetes.