Outcomes and Complications of Corticosteroid Injection of Rheumatoid Nodules.

Objective: Rheumatoid nodules (RN), a classic cutaneous extra-articular manifestation of rheumatoid arthritis, can often cause discomfort or cosmetic embarrassment. This research determined the effectiveness and complications of corticosteroid injection of the RN. Methods: Using a repeated measure design, 66 consecutive symptomatic RN were measured, underwent corticosteroid injection with 1 to 2mL of a 50:50 mixture of 1% lidocaine and triamcinolone acetonide (20-40mg), and then reassessed at four months for softening, reduction in size, and complications, including infection. Results: The mean age of our patient group was 53.3±10.6 years; 45 percent were Hispanic, 55 percent were non-Hispanic White, 100 percent were seropositive (rheumatoid factor and/or anti-CCP antibody), and 87.5 percent were female. Baseline mean RN diameter was 0.50±0.51cm and four months after injection was reduced to 0.29±0.33cm (decreased 42% or 0.21±0.57cm reduction, 95% CI: 0.46 <0.21< 0.37, p=0.013), 100 percent (66/66) were less painful, and 77 percent (51/66) were palpably softened. However, 70 percent (46/66) demonstrated cutaneous atrophy and/or hypopigmentation at four months, 53 percent (35/66) nodules recurred within 12 months, and 47 percent (31/66) nodules were eventually surgically removed. Limitations: Two (3%) of the larger RN (2.5cm on the olecranon and 2cm on the 2nd toe) became infected and failed antibiotic therapy, necessitating surgical excision for complete resolution. Conclusion: For short-term symptomatic relief, smaller RN can be safely injected with triamcinolone. Large symptomatic RN (≥2cm) are at greater risk of infection; thus, in these cases, lower corticosteroid doses or surgical excision may be preferred. In the long-term, effective systemic antirheumatic therapy with treat-to-target is the best approach.

Intraarticular injection of the interphalangeal joint for therapy of digital mucoid cysts.

Mucoid cysts are associated with osteoarthritis (OA) of the digital joints and frequently recur after needle drainage, injection, or surgical ablation. This study determined whether intraarticular injection of the adjacent interphalangeal joint rather than the cyst itself might be effective in resolving digital mucoid cysts. Using paired case series design and sterile technique, 25 consecutive OA digital joints with an adjacent mucoid cyst underwent dorsal non-transtendinous intraarticular injection with a 25-gauge needle and 20-mg triamcinolone acetonide, followed by puncture and manual expression of cyst fluid. Patient pain was measured with the 10-cm Visual Analogue Pain Scale prior to the procedure and at 6 months. Cyst resolution was determined at 6 months and 3 years. The subjects were 61.0 ± 7.7 years old and 60% (15/25) female. Mucoid cysts were adjacent to 19 distal interphalangeal, 3 metacarpophalangeal, and 3 interphalangeal joints. Pre-procedural pain was 4.7 ± 1.0; procedural pain was 6.2 ± 0.6 cm, and post-procedural pain at 6 months was 1.2 ± 0.8 cm (74.5% reduction, 95% CI of difference: 3.0 < 3.5 < 4.0 (p < 0.0001)). 84% (21/25) of the cysts resolved at 6 months; however, 60% (15/25) of the mucoid cysts recurred within 3 years and required retreatment (14 adjacent joints re-injected and 1 ablative cyst surgery). No complications were noted. Intraarticular corticosteroid injection using a dorsal non-transtendinous approach of the joint adjacent to a mucoid cyst is effective resolving cysts and reducing pain at 6 months; however, 60% of mucoid cysts reoccur within 3 years and may require reinjection or surgery.Trial registration: This was not a clinical trial.

Enhanced arthrocentesis of the effusive knee with pneumatic compression.

AIM: Complete arthrocentesis of the effusive knee ameliorates patient pain, reduces intra-articular and intraosseous pressure, removes inflammatory cytokines, and has been shown to substantially improve the therapeutic outcomes of intra-articular injections. However, conventional arthrocentesis incompletely decompresses the knee, leaving considerable residual synovial fluid in the intra-articular space. The present study determined whether external pneumatic circumferential compression of the effusive knee permitted more successful arthrocentesis and complete joint decompression. METHODS: Using a paired sample design, 50 consecutive effusive knees underwent conventional arthrocentesis and then arthrocentesis with pneumatic compression. Pneumatic compression was applied to the superior knee using a conventional thigh blood pressure cuff inflated to 100 mm Hg which compressed the suprapatellar bursa and patellofemoral joint, forcing fluid from the superior knee to the anterolateral portal where the fluid could be accessed. Arthrocentesis success and fluid yield in mL before and after pneumatic compression were determined. RESULTS: Successful diagnostic arthrocentesis (≥3 mL) of the effusive knee was 82% (41/50) with conventional arthrocentesis and increased to 100% (50/50) with pneumatic compression (P = .001). Synovial fluid yields increased by 144% (19.8 ± 17.1 mL) with pneumatic compression (conventional arthrocentesis; 13.7 ± 16.4 mL, pneumatic compression: 33.4 ± 26.5 mL; 95% CI: 10.9 < 19.7 < 28.9 mL, P < .0001). CONCLUSIONS: Conventional arthrocentesis routinely does not fully decompress the effusive knee. External circumferential pneumatic compression markedly improves arthrocentesis success and fluid yield, and permits complete decompression of the effusive knee. Pneumatic compression of the effusive knee with a thigh blood pressure cuff is an inexpensive and widely available technique to improve arthrocentesis outcomes.

Effects of voluntary exercise duration on myocardial ischaemic tolerance, kinase signaling and gene expression.

AIM: Exercise is cardioprotective, though optimal interventions are unclear. We assessed duration dependent effects of exercise on myocardial ischemia-reperfusion (I-R) injury, kinase signaling and gene expression. METHODS: Responses to brief (2 day; 2EX), intermediate (7 and 14 day; 7EX and 14EX) and extended (28 day; 28EX) voluntary wheel running (VWR) were studied in male C57Bl/6 mice. Cardiac function, I-R tolerance and survival kinase signaling were assessed in perfused hearts. KEY FINDINGS: Mice progressively increased running distances and intensity, from 2.4 ± 0.2 km/day (0.55 ± 0.04 m/s) at 2-days to 10.6 ± 0.4 km/day (0.72 ± 0.06 m/s) after 28-days. Myocardial mass and contractility were modified at 14-28 days VWR. Cardioprotection was not 'dose-dependent', with I-R tolerance enhanced within 7 days and not further improved with greater VWR duration, volume or intensity. Protection was associated with AKT, ERK1/2 and GSK3ß phosphorylation, with phospho-AMPK selectively enhanced with brief VWR. Gene expression was duration-dependent: 7 day VWR up-regulated glycolytic (Pfkm) and down-regulated maladaptive remodeling (Mmp2) genes; 28 day VWR up-regulated caveolar (Cav3), mitochondrial biogenesis (Ppargc1a, Sirt3) and titin (Ttn) genes. Interestingly, I-R tolerance in 2EX/2SED groups improved vs. groups subjected to longer sedentariness, suggesting transient protection on transition to housing with running wheels. SIGNIFICANCE: Cardioprotection is induced with as little as 7 days VWR, yet not enhanced with further or faster running. This protection is linked to survival kinase phospho-regulation (particularly AKT and ERK1/2), with glycolytic, mitochondrial, caveolar and myofibrillar gene changes potentially contributing. Intriguingly, environmental enrichment may also protect via similar kinase regulation.

Cardiac perturbations after high-intensity exercise are attenuated in middle-aged compared with young endurance athletes: diminished stress or depleted stimuli?

Strenuous exercise elicits transient functional and biochemical cardiac imbalances. Yet, the extent to which these responses are altered owing to aging is unclear. Accordingly, echocardiograph-derived left ventricular (LV) and right ventricular (RV) global longitudinal strain (GLS) and high-sensitivity cardiac troponin I (hs-cTnI) were assessed before (pre) and after (post) a 60-min high-intensity cycling race intervention (CRIT60) in 11 young (18-30 yr) and 11 middle-aged (40-65 yr) highly trained male cyclists, matched for cardiorespiratory fitness. LV and RV GLS were measured at rest and during a semirecumbent exercise challenge performed at the same intensity (young: 93 ± 10; middle-aged: 85 ± 11 W, P = 0.60) pre- and post-CRIT60. Augmentation (change from rest-to-exercise challenge) of LV GLS (pre: -2.97 ± 0.65; post: -0.82 ± 0.48%, P = 0.02) and RV GLS (pre: -2.08 ± 1.28; post: 3.08 ± 2.02%, P = 0.01) was attenuated and completely abolished, in the young following CRIT60, while augmentation of LV GLS (pre: -3.21 ± 0.41; post: -3.99 ± 0.55%, P = 0.22) and RV GLS (pre: -3.47 ± 1.44; post: -1.26 ± 1.00%, P = 0.27) was preserved in middle-aged following CRIT60. While serum hs-cTnI concentration increased followingCRIT60 in the young (pre: 7.3 ± 1.6; post: 17.7 ± 1.6 ng/L, P < 0.01) and middle-aged (pre: 4.5 ± 0.6; post: 10.7 ± 2.0 ng/L, P < 0.01), serum hs-cTnI concentration increased to a greater extent in the young than in the middle-aged following CRIT60 (P < 0.01). These findings suggest that functional and biochemical cardiac perturbations induced by high-intensity exercise are attenuated in middle-aged relative to young individuals. Further study is warranted to determine whether acute exercise-induced cardiac perturbations alter the adaptive myocardial remodeling response.NEW & NOTEWORTHY High-intensity endurance exercise elicits acute cardiac imbalances that may be an important stimulus for adaptive cardiac remodeling. This study highlights that following a bout of high-intensity exercise that is typical of routine day-to-day cycling training, exercise-induced autonomic, biochemical, and functional cardiac imbalances are attenuated in middle-aged relative to young well-trained cyclists. These findings suggest that aging may alter exercise-induced stress stimulus response that initiates cardiac remodeling in athlete's heart.

Utilizing heart rate variability to predict ICU patient outcome in traumatic brain injury.

BACKGROUND: Prediction of patient outcome in medical intensive care units (ICU) may help for development and investigation of early interventional strategies. Several ICU scoring systems have been developed and are used to predict clinical outcome of ICU patients. These scores are calculated from clinical physiological and biochemical characteristics of patients. Heart rate variability (HRV) is a correlate of cardiac autonomic regulation and has been evident as a marker of poor clinical prognosis. HRV can be measured from the electrocardiogram non-invasively and monitored in real time. HRV has been identified as a promising 'electronic biomarker' of disease severity. Traumatic brain injury (TBI) is a subset of critically ill patients admitted to ICU, with significant morbidity and mortality, and often difficult to predict outcomes. Changes of HRV for brain injured patients have been reported in several studies. This study aimed to utilize the continuous HRV collection from admission across the first 24 h in the ICU in severe TBI patients to develop a patient outcome prediction system. RESULTS: A feature extraction strategy was applied to measure the HRV fluctuation during time. A prediction model was developed based on HRV measures with a genetic algorithm for feature selection. The result (AUC: 0.77) was compared with earlier reported scoring systems (highest AUC: 0.76), encouraging further development and practical application. CONCLUSIONS: The prediction models built with different feature sets indicated that HRV based parameters may help predict brain injury patient outcome better than the previously adopted illness severity scores.

Marked Disparity in Regional and Transmural Cardiac Mechanics in the Athlete's Heart.

INTRODUCTION: Regional heterogeneity of the human heart plays an important role in left ventricular (LV) and right ventricular (RV) function and may contribute to enhanced myocardial efficiency in the athlete's heart. PURPOSE: This study comprehensively characterized regional and transmural myocardial tissue deformation (strain) in recreationally active (RA) and endurance-trained (ET) men to determine if regional nonuniformity evolves alongside morphological adaptations associated with endurance training. METHODS: Echocardiography was used to measure LV and RV global, regional (apical, mid, basal) and transmural (endocardial, epicardial) longitudinal strain in 30 endurance-trained (ET) (age, 31 ± 2 yr; body mass index, 23.1 ± 0.5 kg·m; V˙O2peak, 60.2 ± 6.5 mL·kg·min) and 30 RA (age: 29 ± 2 yr; body mass index, 23.4 ± 0.4 kg·m; V˙O2peak: 42.6 ± 4.6 mL·kg·min). Nonuniformity was characterized using apex-to-base and transmural (endocardial-to-epicardial) strain gradients. RESULTS: Global longitudinal strain was similar in ET and RA in the left (-17.4% ± 0.4% vs -17.8% ± 0.5%, P = 0.662) and right ventricle (-25.8% ± 0.8% vs 26.4% ± 1.0%, P = 0.717). The apex-to-base strain gradient was greater in ET than RA in the left (-6.5% ± 0.7% vs -2.7% ± 0.8%, P = 0.001) and right ventricle (-9.6% ± 1.8% vs -3.0% ± 1.6%, P = 0.010). The LV transmural strain gradient was greater than RV in both groups, but similar in ET and RA (-4.7% ± 0.2% vs -4.7% ± 0.2%, P = 0.850), whereas RV transmural strain gradient was greater in ET than RA (-3.4% ± 0.3% vs -1.6% ± 0.4%, P = 0.003). RV apex-to-base and transmural strain gradients correlated with RV end-diastolic area (R = 0.536 & 0.555, respectively, P < 0.01) and V˙O2peak (R = 0.415 & 0.677, respectively, P < 0.01). CONCLUSIONS: Transmural nonuniformity is more pronounced in the left ventricle than the RV free wall; however, RV functional nonuniformity develops markedly after endurance training. Differences in myocardial architecture and exercise-induced wall stress in the left and right ventricles are possible explanations for the marked functional nonuniformity throughout the myocardium and in response to endurance exercise training.

Extractable synovial fluid in inflammatory and non-inflammatory arthritis of the knee.

INTRODUCTION/OBJECTIVES: We hypothesized that mechanical compression of the knee in rheumatoid arthritis (RA) would mobilize occult extractable fluid and improve arthrocentesis success. METHODS: Sixty-seven consecutive knees with RA and 186 knees with OA and were included. Conventional arthrocentesis was performed and success and volume (milliliters) determined; the needle was left intraarticularly, and mechanical compression was applied with an elastomeric knee brace. Arthrocentesis was then resumed until fluid return ceased. Fluid was characterized as to volume and cell counts. RESULTS: In the RA, knee mechanical compression decreased failed diagnostic arthrocentesis from 56.7% (38/67) to 26.9% (18/67) (- 47.4%, p = 0.003) and increased absolute arthrocentesis yield from 4.7 ± 10.3 ml to 9.8 ± 9.8 ml (108% increase, 95% CI - 8.5 < - 5.1 < - 1.7 p = 0.0038). Total extractable fluid yield was 96% greater in RA (9.8 ± 9.8 ml) than OA (5.0 ± 9.4 ml, p = 0.0008), and occult extractable fluid was 77% greater in RA than OA (RA 5.3 ± 8.7 ml, OA 3.0 ± 5.5 ml, p = 0.046). Large effusions versus small effusions in RA demonstrated increased neutrophils in synovial fluid (p = 0.04) but no difference in radiologic arthritis grade (p = 0.87). In contrast, large effusions versus small effusions in OA demonstrated no difference in neutrophils in synovial fluid (p = 0.87) but significant different radiologic arthritis grade (p = 0.04). CONCLUSION: Mechanical compression improves the success of diagnostic and therapeutic knee arthrocentesis in both RA and OA. Large effusions in RA are associated with increased neutrophil counts but not arthritis grade; in contrast, large effusions in OA are associated with more severe arthritis grades but not increased neutrophil counts. Key points• Mechanical compression of the painful knee improves arthrocentesis success and fluid yield in both rheumatoid arthritis and osteoarthritis.• The painful rheumatoid knee contains approximately 100% more fluid than the osteoarthritic knee.• Large effusions in the osteoarthritic knee are characterized by higher grades of mechanical destruction but not increased neutrophil counts.• In contrast, large effusions in the rheumatoid knee are characterized by higher synovial fluid neutrophil counts but not the grade of mechanical destruction, indicating different mechanisms of effusion formation in rheumatoid arthritis versus osteoarthritis.

Gene networks in skeletal muscle following endurance exercise are coexpressed in blood neutrophils and linked with blood inflammation markers.

It remains incompletely understood whether there is an association between the transcriptome profiles of skeletal muscle and blood leukocytes in response to exercise or other physiological stressors. We have previously analyzed the changes in the muscle and blood neutrophil transcriptome in eight trained men before and 3, 48, and 96 h after 2 h cycling and running. Because we collected muscle and blood in the same individuals and under the same conditions, we were able to directly compare gene expression between the muscle and blood neutrophils. Applying weighted gene coexpression network analysis (WGCNA) as an advanced network-driven method to these original data sets enabled us to compare the muscle and neutrophil transcriptomes in a rigorous and systematic manner. Two gene networks were identified that were preserved between skeletal muscle and blood neutrophils, functionally related to mitochondria and posttranslational processes. Strong preservation measures (Zsummary > 10) for both muscle-neutrophil gene networks were evident within the postexercise recovery period. Muscle and neutrophil gene coexpression was strongly correlated in the mitochondria-related network (r = 0.97; P = 3.17E-2). We also identified multiple correlations between muscular gene subnetworks and exercise-induced changes in blood leukocyte counts, inflammation, and muscle damage markers. These data reveal previously unidentified gene coexpression between skeletal muscle and blood neutrophils following exercise, showing the value of WGCNA to understand exercise physiology. Furthermore, these findings provide preliminary evidence in support of the notion that blood neutrophil gene networks may potentially help us to track physiological and pathophysiological changes in the muscle.NEW & NOTEWORTHY By using weighted gene coexpression network analysis, an advanced bioinformatics method, we have identified previously unknown, functional gene networks that are preserved between skeletal muscle and blood neutrophils during recovery from exercise. These novel preliminary data suggest that muscular gene networks are coexpressed in blood leukocytes following physiological stress. This is a step forward toward the development of blood neutrophil gene subnetworks as part of blood biomarker panels to assess muscle health and disease.

Impact of high-intensity endurance exercise on regional left and right ventricular myocardial mechanics.

AIMS: Strenuous endurance exercise acutely increases myocardial wall stress and evokes transient functional cardiac perturbations. However, it is unclear whether exercise-induced functional cardiac disturbances are ubiquitous throughout the myocardium or are segment specific. The aim of this study was to examine the influence of high-intensity endurance exercise on global and segmental left (LV) and right (RV) ventricular tissue deformation (strain). METHODS AND RESULTS: Echocardiography was used to measure strain in 23 active men (age: 28 ± 2 years; VO2 peak: 4.5 ± 0.7 L min-1) at rest and during a standardized low-intensity exercise challenge, before and after a 90-min high-intensity endurance cycling intervention. Following the cycling intervention, LV and RV global strain decreased at rest (LV: -18.4 ± 0.4% vs. -17.7 ± 0.4%, P < 0.05; RV: -27.6 ± 0.7% vs. -26.4 ± 0.6%, P < 0.05) and by a greater extent during the low-intensity exercise challenge (LV: -21.3 ± 0.4% vs. -19.2 ± 0.5%, P < 0.01; RV: -28.4 ± 0.8% vs. -23.5 ± 0.9%, P < 0.01). Reductions in LV strain were unique to regions of RV attachment (e.g. LV septum: -24.4 ± 0.5% vs. -21.4 ± 0.6%, P < 0.01) with lateral (-18.9 ± 0.4% vs. -18.4 ± 0.5%) and posterior segments (-19.5 ± 0.4% vs. -18.8 ± 0.7%) unaffected. Similarly, augmentation of strain from rest to exercise was abolished in the RV free wall (-1.1 ± 1.0% vs. 2.9 ± 1.2%, P < 0.01), reduced in the septum (-4.6 ± 0.4% vs. -2.4 ± 0.5%, P < 0.01), and unchanged in the lateral (-1.2 ± 0.6% vs. -0.9 ± 0.6%) and posterior walls (-1.7 ± 0.6% vs. -1.3 ± 0.7%). CONCLUSION: Changes in ventricular strain following high-intensity exercise are more profound in the right ventricle than in the left ventricle. Reductions in LV strain were unique to the septal myocardium and may reflect ventricular interactions secondary to exercise-induced RV dysfunction.

Regular walking improves plasma protein concentrations that promote blood hyperviscosity in women 65-74 yr with type 2 diabetes.

BACKGROUND: The purpose of the present study was to investigate the effects of regular treadmill walking on plasma factors that increase low-shear blood viscosity and red blood cell aggregation in older women with type 2 diabetes. METHODS: Eighteen women with type 2 diabetes (age: 69±3 yr; body mass index: 30.5±5.0 kg⋅m-2) performed 12-wk of 120 min⋅wk-1 of supervised treadmill walking at an intensity equivalent to the gas-exchange threshold. Peak exercise values, anthropometry and blood indices of diabetic status, markers of inflammation, and plasma fibrinogen were analysed during a 6-wk pre-training 'control' period, and then after 6 and 12-wk of regular walking. RESULTS: Regular walking significantly increased peak oxygen uptake (p = 0.01). Body mass, waist to hip ratio, and glycaemic control did not change. Systolic and diastolic blood pressures decreased by 8.5% (p < 0.01) and 7.2% (p < 0.01) respectively, cholesterol to high-density lipoprotein (HDL) ratio decreased by 9.6% (p = 0.01), and HDL concentration significantly increased (p = 0.01). While 12 wk of regular walking did not significantly alter plasma concentrations of interleukin-6 (IL-6), tumour necrosis factor-α, or C-reactive protein, plasma fibrinogen concentration decreased by 6.9% (p < 0.01) and plasma interleukin-10 (IL-10) concentration increased from 1.15±0.32 to 1.62±0.22 mmol⋅L-1 (p < 0.04). CONCLUSIONS: Improved plasma inflammatory profile and decreased plasma fibrinogen concentration is induced by regular walking, independent of glycaemic control. These factors may mediate the improved haemorheology associated with exercise training in metabolic disorders.

Influence of exercise intensity and duration on functional and biochemical perturbations in the human heart.

KEY POINTS: Strenuous endurance exercise induces transient functional and biochemical cardiac perturbations that persist for 24-48 h. The magnitude and time-course of exercise-induced reductions in ventricular function and increases in cardiac injury markers are influenced by the intensity and duration of exercise. In a human experimental model, exercise-induced reductions in ventricular strain and increases in cardiac troponin are greater, and persist for longer, when exercise is performed within the heavy- compared to moderate-intensity exercise domain, despite matching for total mechanical work. The results of the present study help us better understand the dose-response relationship between endurance exercise and acute cardiac stress/injury, a finding that has implications for the prescription of day-to-day endurance exercise regimes. ABSTRACT: Strenuous endurance exercise induces transient cardiac perturbations with ambiguous health outcomes. The present study investigated the magnitude and time-course of exercise-induced functional and biochemical cardiac perturbations by manipulating the exercise intensity-duration matrix. Echocardiograph-derived left (LV) and right (RV) ventricular global longitudinal strain (GLS), and serum high-sensitivity cardiac troponin (hs-cTnI) concentration, were examined in 10 males (age: 27 ± 4 years; V̇O2, peak : 4.0 ± 0.8 l min(-1) ) before, throughout (50%, 75% and 100%), and during recovery (1, 3, 6 and 24 h) from two exercise trials. The two exercise trials consisted of 90 and 120 min of heavy- and moderate-intensity cycling, respectively, with total mechanical work matched. LVGLS decreased (P < 0.01) during the 90 min trial only, with reductions peaking at 1 h post (pre: -19.9 ± 0.6%; 1 h post: -18.5 ± 0.7%) and persisting for >24 h into recovery. RVGLS decreased (P < 0.05) during both exercise trials with reductions in the 90 min trial peaking at 1 h post (pre: -27.5 ± 0.7%; 1 h post: -25.1 ± 0.8%) and persisting for >24 h into recovery. Serum hs-cTnI increased (P < 0.01) during both exercise trials, with concentrations peaking at 3 h post but only exceeding cardio-healthy reference limits (14 ng l(-1) ) in the 90 min trial (pre: 4.2 ± 2.4 ng l(-1) ; 3 h post: 25.1 ± 7.9 ng l(-1) ). Exercise-induced reductions in ventricular strain and increases in cardiac injury markers persist for 24 h following exercise that is typical of day-to-day endurance exercise training; however, the magnitude and time-course of this response can be altered by manipulating the intensity-duration matrix.

Reproducibility of Echocardiograph-Derived Multilevel Left Ventricular Apical Twist Mechanics.

Left ventricular (LV) twist mechanics are routinely assessed via echocardiography in clinical and research trials investigating the function of obliquely oriented myocardial fibers. However, echocardiograph-derived measures of LV twist may be compromised by nonstandardized acquisition of the apical image. This study examined the reproducibility of echocardiograph-derived parameters of apical twist mechanics at multiple levels of the apical myocardium. Two sets of 2D LV parasternal short-axis images were obtained in 30 healthy subjects (24 men; 19-57 year) via echocardiography. Images were acquired immediately distal to the papillary muscles (apical image 1), immediately above the point of LV cavity obliteration at end systole (apical image 3), and midway between apical image 1 and apical image 3 (apical image 2). Repeat scans were performed within 1 hour, and twist mechanics (rotation and rotation rate) were calculated via frame-by-frame tracking of natural acoustic echocardiographic markers (speckle tracking). The magnitude of apical rotation increased progressively toward the apex (apical image 1: 4.2 ± 2.1°, apical image 2: 7.2 ± 3.9°, apical image 3: 11.8 ± 4.6°). apical images 1, 2, and 3 each had moderate to good correlations between repeat scans (ICC: 0.531-0.856). When apical images 1, 2, and 3 were averaged, rotation was 7.7 ± 2.7° and between-scan correlation was excellent (ICC: 0.910). Similar results were observed for systolic and diastolic rotation rates. Averaging multiple standardized apical images, tending progressively toward the apex, generated the most reproducible rotation indices and may be optimal for the assessment of LV twist mechanics across therapeutic, interventional, and research studies; however, care should be taken given the influence of acquisition level on the magnitude of apical rotation.

Evaluation of a 7-Gene Genetic Profile for Athletic Endurance Phenotype in Ironman Championship Triathletes.

Polygenic profiling has been proposed for elite endurance performance, using an additive model determining the proportion of optimal alleles in endurance athletes. To investigate this model's utility for elite triathletes, we genotyped seven polymorphisms previously associated with an endurance polygenic profile (ACE Ins/Del, ACTN3 Arg577Ter, AMPD1 Gln12Ter, CKMM 1170bp/985+185bp, HFE His63Asp, GDF8 Lys153Arg and PPARGC1A Gly482Ser) in a cohort of 196 elite athletes who participated in the 2008 Kona Ironman championship triathlon. Mean performance time (PT) was not significantly different in individual marker analysis. Age, sex, and continent of origin had a significant influence on PT and were adjusted for. Only the AMPD1 endurance-optimal Gln allele was found to be significantly associated with an improvement in PT (model p = 5.79 x 10-17, AMPD1 genotype p = 0.01). Individual genotypes were combined into a total genotype score (TGS); TGS distribution ranged from 28.6 to 92.9, concordant with prior studies in endurance athletes (mean±SD: 60.75±12.95). TGS distribution was shifted toward higher TGS in the top 10% of athletes, though the mean TGS was not significantly different (p = 0.164) and not significantly associated with PT even when adjusted for age, sex, and origin. Receiver operating characteristic curve analysis determined that TGS alone could not significantly predict athlete finishing time with discriminating sensitivity and specificity for three outcomes (less than median PT, less than mean PT, or in the top 10%), though models with the age, sex, continent of origin, and either TGS or AMPD1 genotype could. These results suggest three things: that more sophisticated genetic models may be necessary to accurately predict athlete finishing time in endurance events; that non-genetic factors such as training are hugely influential and should be included in genetic analyses to prevent confounding; and that large collaborations may be necessary to obtain sufficient sample sizes for powerful and complex analyses of endurance performance.

Altered ventricular mechanics after 60 min of high-intensity endurance exercise: insights from exercise speckle-tracking echocardiography.

Transient reductions in myocardial strain coupled with cardiac-specific biomarker release have been reported after prolonged exercise (>180 min). However, it is unknown if 1) shorter-duration exercise (60 min) can perturb cardiac function or 2) if exercise-induced reductions in strain are masked by hemodynamic changes that are associated with passive recovery from exercise. Left ventricular (LV) and right ventricular global longitudinal strain (GLS), LV torsion, and high-sensitivity cardiac troponin T were measured in 15 competitive cyclists (age: 28 ± 3 yr, peak O2 uptake: 4.8 ± 0.6 l/min) before and after a 60-min high-intensity cycling race intervention (CRIT60). At both time points (pre- and post-CRIT60), strain and torsion were assessed at rest and during a standardized low-intensity exercise challenge (power output: 96 ± 8 W) in a semirecumbent position using echocardiography. During rest, hemodynamic conditions were different from pre- to post-CRIT60 (mean arterial pressure: 96 ± 1 vs. 86 ± 2 mmHg, P < 0.001), and there were no changes in strain or torsion. In contrast, during the standardized low-intensity exercise challenge, hemodynamic conditions were unchanged from pre- to post-CRIT60 (mean arterial pressure: 98 ± 1 vs. 97 ± 1 mmHg, not significant), but strain decreased (left ventricular GLS: -20.3 ± 0.5% vs. -18.5 ± 0.4%, P < 0.01; right ventricular GLS: -26.4 ± 1.6% vs. -22.4 ± 1.5%, P < 0.05), whereas LV torsion remained unchanged. Serum high-sensitivity cardiac troponin T increased by 345% after the CRIT60 (6.0 ± 0.6 vs. 20.7 ± 6.9 ng/l, P < 0.05). This study demonstrates that exercise-induced functional and biochemical cardiac perturbations are not confined to ultraendurance sporting events and transpire during exercise that is typical of day-to-day training undertaken by endurance athletes. The clinical significance of cumulative exposure to endurance exercise warrants further study.

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.

Mitochondrial function and increased convective O2 transport: implications for the assessment of mitochondrial respiration in vivo.

Although phosphorus magnetic resonance spectroscopy (31P-MRS)-based evidence suggests that in vivo peak mitochondrial respiration rate in young untrained adults is limited by the intrinsic mitochondrial capacity of ATP synthesis, it remains unknown whether a large, locally targeted increase in convective O2 delivery would alter this interpretation. Consequently, we examined the effect of superimposing reactive hyperemia (RH), induced by a period of brief ischemia during the last minute of exercise, on oxygen delivery and mitochondrial function in the calf muscle of nine young adults compared with free-flow conditions (FF). To this aim, we used an integrative experimental approach combining 31P-MRS, Doppler ultrasound imaging, and near-infrared spectroscopy. Limb blood flow [area under the curve (AUC), 1.4 ± 0.8 liters in FF and 2.5 ± 0.3 liters in RH, P < 0.01] and convective O2 delivery (AUC, 0.30 ± 0.16 liters in FF and 0.54 ± 0.05 liters in RH, P < 0.01), were significantly increased in RH compared with FF. RH was also associated with significantly higher capillary blood flow (P < 0.05) and faster tissue reoxygenation mean response times (70 ± 15 s in FF and 24 ± 15 s in RH, P < 0.05). This resulted in a 43% increase in estimated peak mitochondrial ATP synthesis rate (29 ± 13 mM/min in FF and 41 ± 14 mM/min in RH, P < 0.05) whereas the phosphocreatine (PCr) recovery time constant in RH was not significantly different (P = 0.22). This comprehensive assessment of local skeletal muscle O2 availability and utilization in untrained subjects reveals that mitochondrial function, assessed in vivo by 31P-MRS, is limited by convective O2 delivery rather than an intrinsic mitochondrial limitation.

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.

The genetics of endurance: frequency of the ACTN3 R577X variant in Ironman World Championship athletes.

OBJECTIVES: To investigate the frequency of the ACTN3 R577X polymorphism in elite endurance triathletes, and whether ACTN3 R577X is significantly associated with performance time. DESIGN: Cross-sectional study. METHODS: Saliva samples, questionnaires, and performance times were collected for 196 elite endurance athletes who participated in the 2008 Kona Ironman championship triathlon. Athletes were of predominantly North American, European, and Australian origin. A one-way analysis of variance was conducted to compare performance times between genotype groups. Multiple linear regression analysis was performed to model the effect of questionnaire variables and genotype on performance time. Genotype and allele frequencies were compared to results from different populations using the chi-square test. RESULTS: Performance time did not significantly differ between genotype groups, and age, sex, and continent of origin were significant predictors of finishing time (age and sex: p<5×10(-6); continent: p=0.003) though genotype was not. Genotype and allele frequencies obtained (RR 26.5%, RX 50.0%, XX 23.5%, R 51.5%, X 48.5%) were found to be not significantly different from Australian, Spanish, and Italian endurance athletes (p>0.05), but were significantly different from Kenyan, Ethiopian, and Finnish endurance athletes (p<0.01). CONCLUSIONS: Genotype and allele frequencies agreed with those reported for endurance athletes of similar ethnic origin, supporting previous findings for an association between 577X allele and endurance. However, analysis of performance time suggests that ACTN3 does not alone influence endurance performance, or may have a complex effect on endurance performance due to a speed/endurance trade-off.