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UK university undergraduate programs are compared by independent subject-specific rankings (Complete, Guardian, and Times), based on data from the National Student Survey, Higher Education Statistics Agency, Universities and Colleges Admissions Service, Research Excellence Framework, and the universities. The sports and exercise science program at the University of Glasgow has steadily risen to currently rank as the top UK program. This investigation aimed to identify the underlying factors that explain this. Therefore, we obtained underlying scores for entry standard, student satisfaction, research foundation, graduate prospects, staff-to-student ratio, expenditure/student, continuation, program support to students, and teaching quality from the ranking providers for years 2010-2024, and statistically modeled which factors significantly affected the rankings. We found that entry standards and graduate prospects strongly correlated significantly with ranking results. Principal component analysis indicated that a model of graduate prospects and entry standards explained 66.2% of the variance in ranking results. Multiple linear regression with all underlying factors included in the model indicated they explained 78% ( R 2  = 0.78) of the total variance, while stepwise elimination of insignificant factors identified graduate prospects as the sole factor that significantly affected outcome by explaining 71% ( R 2  = 0.71) of the variance. Therefore, the primary predictor of ranking success in UK university league tables for sports science is graduates' professional success (graduate prospects). NEW & NOTEWORTHY University rankings are used by applicants and stakeholders to judge programs, including undergraduate studies. In the rankings, undergraduate UK programs are compared and contrasted against each other based on how they score for criteria that affect student life and future prospects. Here, we determined the relative influence of those criteria and found that graduate prospects, how students professionally benefit from their study after graduation, is the factor that matters most for the ranking results.

Abstract: Carpels, T, Scobie, N, Macfarlane, NG, and Kemi, OJ. Mind the gap: comparison of external load and load variation between a reserve team in a 1-game week microcycle and its first team in a 2-game week microcycle within an elite professional soccer club. J Strength Cond Res 38(5): e235-e242, 2024-The aim of this study was to quantify and compare weekly external load and within-week load variation of reserve team players (RES) in a 1-game week microcycle to first team players (FT) in a 2-game week microcycle within the same professional soccer club. External load data were collected between 2017 and 2020 for the following parameters: duration, total distance (TD), total high-speed distance (THSD; >19.8 km·h -1 ), high-speed distance (HSD; 19.8-25.2 km·h -1 ), sprint distance (SD; >25.2 km·h -1 ), number of sprints (number of efforts >25.2 km·h -1 ), number of high-speed efforts (number of HS efforts >19.8 km·h -1 ), meters per minute (m·min -1 ), and high-speed meters per minute (HS m·min -1 ). First team players were subcategorized into starters (ST) and nonstarters (NST). Intergroup differences in cumulative weekly load and weekly load patterns were statistically analyzed, whereas training monotony (TM) was quantified to assess intragroup, within-week, load variation. Reserve team players showed similar weekly loads to ST, apart from significant differences ( p < 0.005) in duration (8%), TD (21%), and HS efforts (16%). Similar to ST, RES showed greater values than NST ( p < 0.0005) for duration (10%), TD (9%), THSD (30%), HSD (26%), SD (45%), sprints (40%), and HS efforts (22%). Weekly patterns in RES were different from ST and NST ( p < 0.05). Training monotony was highest for NST for all parameters, apart from the number of sprints. Reserve team players need to be prepared to cope with cumulative weekly loads and the lack of recovery between games that ST face. However, when RES become NST, effective loading strategies need to be designed within the limits of 2-game week microcycles to ensure continuous development., (Copyright © 2024 National Strength and Conditioning Association.)

Purpose: This study aimed to examine physiological, mechanical and perceptual loading in small-sided games using different relative playing areas with balanced and unbalanced player numbers., Methods: Data were collected in twelve elite youth male soccer players and included heart rate and standard time-motion outputs using commercial GPS., Results: The data demonstrated higher cardiovascular, physical and perceptual demands with increasing pitch size (e.g. average HR was 88.7 vs. 86.7% HRmax with 8 vs. 2 high-intensity acceleration in medium vs. small pitch formats. The largest pitch format resulted in a greater accumulation of high-intensity distance (47 ± 30 m), higher peak velocity (25.2 ± 1.6 km.h-1) and a higher distance and frequency of accelerations (35 ± 9 m and 8 ± 3) compared with the smallest pitch (all p < 0.01). In unbalanced games, there was significantly greater average heart rate in the overloaded team (84.4 ± 4.9 vs. 80.4 ± 4.8% HRmax in 4 v. 6)., Conclusion: These data suggest that different game formats including numerical imbalance could be prescribed for squad management to target conditioning stimuli for specific players (e.g. to target a higher training load for players that do not get consistent match exposure).

The purpose of this research was to assess relationships between subjective and external measures of training load in professional youth footballers, whilst accounting for the effect of the stage of the season. Data for ratings of perceived exertion (RPE) and seven global positioning systems (GPS) derived measures were collected from 20 players (age = 17.4 ± 1.3 yrs, height = 178.0 ± 8.1 cm, mass = 71.8 ± 7.2 kg) across a 47-week season. The season was categorised by a pre-season phase, and two competitive phases (Comp1, Comp2). The structure of the data were investigated using principal component analysis. An extraction criterion of component with eigenvalues ≥1.0 was used. Two components were retained for the pre-season period explaining a cumulative variance of 77.1%. Single components were retained for both Comp1 and Comp2 explaining 73.3% and 74.3% of variance, respectively. Identification of single components may suggest that measures are related and can be used interchangeably, however these interpretations should be considered with caution. The identification of multiple components in the pre-season phase suggests that univariate measures may not be sufficient when considering load experienced. These results suggest that factoring load based on measures of volume and intensity should be considered.

The priority for soccer academies is to develop youth players that graduate and transfer directly to their senior squads. The aim of this study was to assess the effectiveness of this direct youth-to-senior pathway by examining the extent to which club-trained players (CTPs) are currently involved in elite male European soccer. Relevant demographic longitudinal studies between 2009 and 2020 conducted by the International Centre for Sports Studies Football Observatory were analysed. The main findings were that the proportion of CTPs in senior squads has decreased from 23% to 17% over this time period, while the proportion of expatriates (EXPs) has increased from 35% to 42%. Moreover, clubs resorted more frequently to making new signings (NS, i.e. association-trained players (ATPs) and/or EXPs), with squad proportion increasing from 37% to 44%, while only launching one debutant (DBT, i.e. CTP with no previous senior experience) on average per season. Similar trends are observed in the evolution of playing time: while the fielding of CTPs remained constant (15%), EXPs and NS are fielded increasingly more (49% and 36%, respectively), despite a positive relationship between CTP match fielding and league ranking, with a Spearman Rank correlation r = 0.712 (95% confidence interval [0.381-0.881]), p < 0.01. In conclusion, young talents are still provided opportunities; however, these are limited and increasingly less frequent at their parent clubs. This potentially suggests a dysfunctional direct youth-to-senior development pathway.

Purpose: To quantify and describe relationships between subjective and external measures of training load in professional youth soccer players., Methods: Data from differential ratings of perceived exertion (dRPE) and 7 measures of external training load were collected from 20 professional youth soccer players over a 46-week season. Relationships were described by repeated-measures correlation, principal component analysis, and factor analysis with oblimin rotation., Results: Significant positive (.44 ≤ r ≤ .99; P < .001) within-individual correlations were obtained across dRPE and all external training load measures. Correlation magnitudes were found to decrease when training load variables were expressed per minute. Principal component analysis provided 2 components, which described 83.3% of variance. The first component, which described 72.9% of variance, was heavily loaded by all measures of training load, while the second component, which described 10.4% of the variance, appeared to have a split between objective and subjective measures of volume and intensity. Exploratory factor analysis identified 4 theoretical factors, with correlations between factors ranging from .5 to .8. These factors could be theoretically described as objective volume, subjective volume, objective running, and objective high-intensity measures. Removing dRPE measures from the analysis altered the structure of the model, providing a 3-factor solution., Conclusions: The dRPE measures are significantly correlated with a range of external training load measures and with each other. More in-depth analysis showed that dRPE measures were highly related to each other, suggesting that, in this population, they would provide practitioners with similar information. Further analysis provided characteristic groupings of variables.

Factors associated with plasma levels of adiponectin and leptin were studied in adult subjects without diabetes from Cotonou in Benin (West-Africa). Seventy (70) men and 45 women were included in the study. Anthropometric variables were measured and a venous blood sample was drawn from each subject, after an overnight fasting period, for measurement of plasma glucose, insulin, leptin, and adiponectin levels. HOMA-IR was determined to assess insulin resistance. Adiponectin and leptin levels were higher in women than in men (with adiponectin 18.48 ± 12.77 vs.7.8 ± 10.39 μg/mL, P < 0.0001, and leptin 30.77 ± 19.16 vs. 8.66 ± 8.24 ng/mL, P < 0.0001). Fasting insulin level and HOMA-IR were also higher in the females. Hyperleptinemia was observed in 66,96% of subjects and hypoadiponectinemia was present in 44.35% of subjects. In both men and women, leptin correlated with age (r = 0.2; P = 0.02), BMI (r = 0.572; P < 0.0001), waist circumference (r = 0.534; P < 0.0001), fasting insulin (r = 0.461; P < 0.001), and HOMA-IR (r = 0.430; P < 0.0001). No significant correlation was observed for adiponectin levels with these variables. Only in women, adiponectin was inversely correlated with fasting glucose (r = -0.423; P < 0.004). These data confirm previous descriptions of leptin but suggest that variations in factors determining serum adiponectin levels observed between ethnicities could also been seen between populations from the same ethnicity., (© 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Game context is widely accepted to influence performance but most data available is 'categorical' and addresses performance rather than activity. This study assessed direct effects of opposition and team ranking in field hockey to establish influences on activity. One hundred and eight (n=108) female field hockey players (age 16-39 years) participated, giving 186 competition and 48 training analyses. Team average distance (mean ± SD) observed in a mid-ranked team during competition ranged from 5,949 ± 611 to 7,719 ± 257 m demonstrating an opposition rank effect (Pearson's r=.71; adjusted R(2)=.42). However, multiple linear regression analysis demonstrated a stronger relationship in lower ranked teams (Pearson's r=.99; adjusted R(2)=.97 through 3-9). In contrast, no team rank effect was observed during randomly monitored competition where team average distance ranged from 5,177 ± 444 to 7,316 ± 241 m (Pearson's r=.15 and adjusted R(2)=.12). In training, however, a team rank effect was observed in distance-related performance indicators where team average distance during small-sided games ranged from 5,877 ± 188 to 3,551 ± 193 m drill (per 70 min) with Pearson's r=.95 and adjusted R(2)=.87. The presence of contextual effects has significant practical implications for team sports where the training load assumed from competition may be overestimated., (Copyright © 2015 Elsevier B.V. All rights reserved.)

This study assessed the relative demands of elite field hockey training and competition to determine whether familiar exercise prescription strategies provide an appropriate training stimulus. Sixteen elite male field hockey players (age, 25 ± 4 years; body mass, 70.9 ± 6.6 kg; and maximal oxygen consumption, 61.0 ± 2.1 ml·kg·min [mean ± SD]) participated in the study. Seventy-five elite level competition and 37 training analyses from 8 games and 4 training sessions were obtained. Training duration was longer than competition and covered a greater total distance (109 ± 2.5 vs. 74 ± 0.3 minutes and 7318 ± 221 vs. 5868 ± 75 m; p < 0.001 in both). The distance covered sprinting and running at high intensity was not different between training and competition (114 ± 6 vs. 116 ± 9 m when sprinting and 457 ± 6 vs. 448 ± 7 m for high-intensity running). More high-intensity accelerations were performed during training than in competition (37 ± 3 vs. 20 ± 2). Despite having lower predicted aerobic capacity and covering less distance in competition than in some previous studies, these data support the suggestion that it is high-intensity activity that differentiates international level competition and further suggests that international players can replicate the intensity of competition during small-sided games.

This study investigated the physiological responses to an intensified period of rugby league competition and the subsequent impact on match performance. The participants were 7 rugby league players competing in an international student tournament. The tournament involved three 80-minute games over a 5-day period, with 48 hours between each match. Baseline measures of upper and lower body neuromuscular functions via a plyometric press-up (PP) and countermovement jump (CMJ), respectively (peak power and peak force were measured), blood creatine kinase (CK), and perceptions of well-being were assessed with a questionnaire. These measures were repeated every morning of the competition; neuromuscular fatigue and CK were additionally assessed within 2 hours after the cessation of each game. During each match, player movements were recorded via global positioning system units. There were meaningful reductions in upper (effect size [ES] = -0.55) and lower body (ES = -0.73) neuromuscular functions, and perceptual well-being (ES = -1.56) and increases in blood CK (ES = 2.32) after game 1. These changes increased in magnitude as the competition progressed. There were large reductions in the relative distance covered in high-speed running (ES = -1.49) and maximal accelerations (ES = -0.85) during game 3. Additionally, moderate reductions in the percentage of successful tackles completed were observed during game 3 (ES = -0.59). Collectively, these results demonstrate that during an intensified period of rugby league competition, characterized by only 48 hours between matches, fatigue will accumulate. This cumulative fatigue may compromise high-intensity match activities such as high-speed running, accelerations, and tackling. Furthermore, CMJs and PPs appear to be sensitive measures for monitoring neuromuscular function in rugby league players.

Background: South Asians are more insulin resistant than Europeans, which cannot be fully explained by differences in adiposity. We investigated whether differences in oxidative capacity and capacity for fatty acid utilisation in South Asians might contribute, using a range of whole-body and skeletal muscle measures., Methodology/principal Findings: Twenty men of South Asian ethnic origin and 20 age and BMI-matched men of white European descent underwent exercise and metabolic testing and provided a muscle biopsy to determine expression of oxidative and lipid metabolism genes and of insulin signalling proteins. In analyses adjusted for age, BMI, fat mass and physical activity, South Asians, compared to Europeans, exhibited; reduced insulin sensitivity by 26% (p = 0.010); lower VO2max (40.6±6.6 vs 52.4±5.7 ml x kg(-1) x min(-1), p = 0.001); and reduced fat oxidation during submaximal exercise at the same relative (3.77±2.02 vs 6.55±2.60 mg x kg(-1) x min(-1) at 55% VO2max, p = 0.013), and absolute (3.46±2.20 vs 6.00±1.93 mg x kg(-1) x min(-1) at 25 ml O(2) x kg(-1) x min(-1), p = 0.021), exercise intensities. South Asians exhibited significantly higher skeletal muscle gene expression of CPT1A and FASN and significantly lower skeletal muscle protein expression of PI3K and PKB Ser473 phosphorylation. Fat oxidation during submaximal exercise and VO2max both correlated significantly with insulin sensitivity index and PKB Ser473 phosphorylation, with VO2max or fat oxidation during exercise explaining 10-13% of the variance in insulin sensitivity index, independent of age, body composition and physical activity., Conclusions/significance: These data indicate that reduced oxidative capacity and capacity for fatty acid utilisation at the whole body level are key features of the insulin resistant phenotype observed in South Asians, but that this is not the consequence of reduced skeletal muscle expression of oxidative and lipid metabolism genes.

Aims: Adiponectin is a fat-derived hormone involved in the regulation of metabolism. Adiponectin concentration is inversely related to body weight and, in animals, causes weight loss. We, therefore, measured adiponectin concentration in patients with heart failure (HF) and cachexia., Methods and Results: Serum adiponectin concentrations were measured in three groups of patients with coronary artery disease (CAD): (i) HF, reduced left ventricular systolic function, and cachexia (n = 10); (ii) HF, reduced systolic function but no cachexia (n = 20); (iii) HF-controls-patients with CAD, no HF, and preserved systolic function (n = 10); and in a healthy control group (n = 7). Patients with HF and cachexia had higher concentrations of adiponectin [23.8 (10.2-37.2) microg/mL] than all other groups: HF-no cachexia 8.1 (0.5-16.6) microg/mL; CAD-controls 7.1 (0.4-13.5) microg/mL; and healthy controls 8.7 (2.5-16.8) microg/mL) (P < 0.05 for each comparison). Adiponectin correlated negatively with body mass index, percentage of body fat, waist circumference and insulin resistance, and positively with B-type natriuretic peptide (BNP) and tumour necrosis factor-alpha., Conclusion: Cachexia in HF is associated with an increase in adiponectin concentration. This may represent preservation of the physiological response to change in body fat but might also suggest that adiponectin plays a role in the pathogenesis of cachexia. The correlation between BNP and adiponectin also raises the possibility that the former might increase the secretion of the latter.

While tobacco smoking is the main risk factor for chronic obstructive pulmonary disease (COPD) only a fraction of smokers go on to develop the disease. We investigated the relationship between the insertion (I)--deletion (D) polymorphisms in the Angiotensin converting enzyme (ACE) gene and the risk of developing COPD in smokers by determining the distribution of the ACE genotypes (DD, ID and II) in 151 life-long male smokers. 74 of the smokers had developed COPD (62 +/- 2 years; FEV1 44 +/- 6% reference) whereas the rest retained normal lung function (56 +/- 2 yrs; FEV1 95 +/- 3% reference). In addition, we genotyped 159 males recruited randomly from the general population. The prevalence of the DD genotype was highest (p = 0.01) in the smokers that developed COPD and its presence was associated with a 2-fold increase in the risk for COPD (OR 2.2; IC95% 1.1 to 5.5). Surprisingly, the 151 individuals in the smoking population did not demonstrate Hardy-Weinberg equilibrium unlike the 159 recruited from the general population. Our results suggest that ACE polymorphisms are associated with both the smoking history of an individual and their risk of developing COPD.

Objective: Whole-body plethysmography is a common method of measuring pulmonary function. Although this technique provides a sensitive measure of pulmonary function, it can be problematic and unsuitable in some patients. The development of more accessible techniques would be beneficial., Methods: A prospective study was performed to validate diaphragm ultrasonography as an alternative to whole-body plethysmography in patients referred for pulmonary function testing. Diaphragm movement and position were assessed by ultrasonography after standard pulmonary function testing using whole-body plethysmography., Results: A wide range of lung function was observed. Standard lung volumes were as follows: total lung capacity, 5.57 +/- 1.31 L, residual volume, 2.27 +/- 0.56 L; and vital capacity, 3.30 +/- 0.98 L (mean +/- SD). The ratio of forced expiratory volume in 1 second to forced vital capacity was calculated as 0.69 +/- 0.08. Ultrasonography showed that mean diaphragm excursion values were 11.1 +/- 3.8 mm (2-dimensional), 14.7 +/- 4.1 mm during quiet breathing (M-mode), and 14.8 +/- 3.9 mm during a maximal sniff (M-mode). The velocity of diaphragm movement rose sharply during the sniff maneuver from 15.2 +/- 5.8 mm/s during quiet breathing to 104.0 +/- 33.4 mm/s. Static 2-dimensional measures of diaphragm position at the end of quiet inspiration or expiration correlated with standard measures of lung volume on plethysmography (eg, a correlation coefficient of 0.83 was obtained with end inspiration and vital capacity). All measures of diaphragm movement (whether by 2-dimensional or M-mode techniques) were poorly correlated with any lung volumes measured., Conclusions: These data suggest that dynamic measurements using diaphragm ultrasonography provide a relatively poor measure of pulmonary function in relation to whole-body plethysmography.

Objectives: Understanding the changed ability of cardiac myofilaments to produce pump work requires knowledge of kinetics of crossbridge function as well as more widely studied parameters such as Ca-sensitivity and isometric force development. We tested the hypothesis that altered crossbridge kinetics contribute to reduced myofilament work in early-stage heart failure (left ventricular dysfunction, LVD)., Methods: The sinusoidal oscillation technique can yield insights into crossbridge function. Dynamic stiffness, oscillatory work and power were assessed in chemically skinned, Ca-activated trabeculae from rabbit ventricles in early-stage failure, 8 weeks after infarction induced by coronary artery ligation (LIG). Results were compared with sham-operated controls (SH). LVD was assessed by echocardiography., Results: Ca-activated force and myofilament Ca-sensitivity were not significantly altered at this early stage of LVD. In maximally Ca-activated preparations, the frequency of minimal dynamic stiffness (f(min)) was 23% lower in LIG. f(min) increases by >80% between pCa 5.8 and 4 in SH but not in LIG. Maximal phase lead and lag angles (between length and tension) were lower in LIG at frequencies near f(min), lowering oscillatory work and power. The Lissajous figures (oscillatory work loops) of imposed length vs. tension are often asymmetric near f(min). The degree of asymmetry was greater in LIG., Conclusions: Reduced capacity for mechanical power, consistent with depressed haemodynamic performance in LVD hearts, is only partially attributable to crossbridge slowing; changes in the phase relationship will also contribute. These changes are not readily attributable to known alterations in contractile protein isoforms. Some deductions are drawn about which steps in the crossbridge cycle are modified in this model of LVD. Altered cardiac myocyte Ca-transients, reported to be associated with LVD, will be translated into pump work by a contractile machinery that is functionally altered, even though isometric force and myofilament Ca-sensitivity might remain near-normal at this stage.

Background: Breathlessness is a common symptom experienced by patients with chronic heart failure (CHF) but its etiology remains controversial. Various molecular and histological adaptations have been reported for the diaphragm in CHF but their functional consequences are poorly described., Aims: This study aims to determine the position and function of the diaphragm in CHF patients., Methods: The diaphragm position was measured, relative to the renal pelvis, by ultrasound in 20 CHF patients and ninety controls matched for age and body mass. The extent and velocity of diaphragm movement was also measured during quiet breathing and sniffing., Results: At the end of expiration, the diaphragm was significantly nearer to the renal pelvis in CHF patients (89.3+/-16.8 vs. 96.3+/-19.2 mm, P<0.05) and also moved further during quiet breathing (18.2+/-4.4 vs. 12.7+/-4.6 mm, P<0.001) and sniffing (23.9+/-7.4 vs. 18.2+/-5.7 mm, P<0.005). Velocity of diaphragm movement was also increased in CHF patients during quiet breathing (26.5+/-8.2 vs. 15.9+/-6.1 mm s(-1), P<0.001)., Conclusions: These data demonstrate that the position and function of the diaphragm is altered in CHF.

Oxidants have been suggested to enhance contractile function in unfatigued muscle. In this study we aimed to determine the effect of oxidants on "chemically skinned" diaphragm muscle fibre bundles. The sarcoplasmic reticulum and contractile proteins were exposed to superoxide anions (O2-) and hydrogen peroxide (H2O2) under controlled conditions. Application of O2-initially increased maximum Ca2+ -activated force but subsequently reduced maximum Ca2+ -activated force without altering myofilament Ca2+ sensitivity. Unlike myocardium, caffeine-induced Ca2+ release from the sarcoplasmic reticulum was also inhibited by O2- exposure in diaphragm fibre bundles. Application of H2O2 also increased maximum Ca2+ -activated force but had additional effects on resting tension (which increased to 25 % of the control maximum Ca2+ -activated force). H2O2 was without effect on myofilament Ca2+ sensitivity or caffeine-induced Ca2+ release from the sarcoplasmic reticulum. These data demonstrate that oxidants can potentiate contractile force in the diaphragm through a direct action on the contractile proteins. The potentiation of force is not sustained, however, and under these conditions the detrimental effects of O2- on Ca2+ release from the sarcoplasmic reticulum combined with the effects of oxidants on the contractile proteins will ultimately compromise excitation-contraction coupling in the diaphragm. Experimental Physiology (2001) 86.2, 161-168.

Abnormal respiratory muscle function is thought to contribute to breathlessness and exercise intolerance in heart failure but little is known about possible alterations in the function of such muscle. We have measured tetanic force and intracellular Ca(2+) concentration ([Ca(2+)](i)) in isolated, arterially perfused hemidiaphragm preparations from a rabbit coronary artery ligation model of heart failure. Increasing stimulation frequency (10-100 Hz) caused a progressive increase of force and [Ca(2+)](i) in control preparations, whereas force and [Ca(2+)](i) only increased between 10 and 25 Hz stimulation (decreasing at higher frequencies) in preparations from ligated animals. Cyclopiazonic acid produced a dose-dependent shift in the relationship between stimulation frequency and [Ca(2+)](i) in control preparations that was similar to the shift observed in the diaphragm of coronary-ligated animals. These data indicate that the in vitro contractile characteristics of the diaphragm are significantly altered in our model and that altered [Ca(2+)](i) regulation contributes to the reduced diaphragm strength observed in heart failure.

This study aimed to determine structural alterations occurring in cardiac myofilaments after exogenous application of oxidants and the effects of oxidants on contractile protein function in a rabbit coronary artery ligation model of heart failure. Myocardial "stiffness" was higher in the ligated animals (Lig) than sham-operated controls (Sh, 4.9+/-1.5 versus 1.6+/-0.8 mN.mm-1). Superoxide anion (O2-) exposure decreased active stiffness in both groups, whereas hypochlorous acid (HOCl) had no effect in Lig but increased stiffness in Sh. Resting stiffness was higher in Lig than Sh (0.6+/-0.2 versus 0.2+/-0.1 mN.mm-1), remaining unchanged after O2- exposure but increasing after HOCl in both groups. The frequency at minimum stiffness was lower in Lig than Sh (0.9+/-0.2 versus 1. 7+/-0.6 Hz) and was reduced in both groups after oxidant exposure. Myofilament calcium sensitivity (pCa50) was not altered by O2- in Sh but increased in Lig (pCa50 increased from 5.41+/-0.05 to 5.56+/-0. 06). Protease contamination in the xanthine oxidase used to generate O2- did not affect myofilament ultrastructure at the concentrations used here. These data demonstrate that contractile proteins from "failed" myocardium have a similar response to exogenously applied oxidants as controls and that application of protease-contaminated xanthine oxidase system does not degrade the contractile protein structure.

Background: Muscle weakness has been suggested to result from the deconditioning that accompanies decreased activity levels in chronic cardiopulmonary diseases. The benefits of standard exercise programmes on exercise capacity and muscular strength in disease and health are well documented and exercise capacity is a significant predictor of survival in patients with chronic heart failure (CHF). Selective respiratory muscle training has been shown to improve exercise tolerance in CHF and such observations have been cited to support the suggestion that respiratory muscle weakness contributes to a reduced exercise capacity (despite biopsies showing the metabolic profile of a well trained muscle)., Aims: This study aimed to determine the effects of selective inspiratory muscle training on patients with chronic coronary artery disease to establish if an improved exercise capacity can be obtained in patients that are not limited in their daily activities., Methods: Nine male patients performed three exercise tests (with respiratory and diaphragm function assessed before the third test) then undertook a 4-week programme of inspiratory muscle training. Exercise tolerance, respiratory and diaphragmatic function were re-assessed after training., Results: Exercise capacity improved from 812+/-42 to 864+/-49 s, P<0.05, and velocity of diaphragm shortening increased (during quiet breathing from 12.8+/-1.6 to 19.4+/-1.1 mm s(-1), P<0.005, and sniffing from 71.9+/-9.4 to 110.0+/-12.3 mm s(-1), P<0.005). In addition, five from nine patients were stopped by breathlessness before training; whereas only one patient was stopped by breathlessness after training., Conclusion: The major findings in this study were that a non-intensive 4-week training programme of resistive breathing in patients with chronic coronary artery disease led to an increase in exercise capacity and a decrease in dyspnoea when assessed by symptom limited exercise testing. These changes were associated with significant increases in the velocity of diaphragmatic excursions during quiet breathing and sniffing. Patients that exhibited small diaphragmatic excursions during quiet breathing were most likely to improve their exercise capacity after the training programme. However, the inspiratory muscle-training programme was not associated with any significant changes in respiratory mechanics when peak flow rate, forced expiratory volume and forced vital capacity were measured. The resistive breathing programme used here resulted in a significant increase in the velocity of diaphragm movement during quiet breathing and sniffing. In other skeletal muscles, speed of contraction can be determined by the relative proportion of fibre types and muscle length (Jones, Round, Skeletal Muscle in Health and Disease. Manchester: University Press, 1990). The intensity of the training programme used here, however, is unlikely to significantly alter muscle morphology or biochemistry. Short-term training studies have shown that there can be increases in strength and velocity of shortening that do not relate to changes in muscle biochemistry or morphology. These changes are attributed to the neural adaptations that occur early in training (Northridge et al., Br. Heart J. 1990; 64: 313-316). Independent of the mechanisms involved, this small, uncontrolled study suggests that inspiratory muscle training may improve exercise capacity, diaphragm function and symptoms of breathlessness in patients with chronic coronary artery disease even in the absence of heart failure.

The response of cardiac SR Ca(2+)-loading to cAMP in failing rabbit and human myocardium was examined. Right ventricular (RV) trabeculae were isolated and mounted for isometric tension measurement. They were treated with saponin to permeabilise the sarcolemma but retain SR function, and bathed in a mock intracellular solution including adenosine triphosphate (ATP) and buffered calcium. Caffeine (10 mM) was used to release calcium from the SR. The amplitude of the caffeine-induced contracture was used as a quantitative gauge of the calcium content of the SR. Trabeculae were isolated from rabbits with coronary ligation-induced heart failure (LIG, n = 11), sham operated controls (SH, n = 10), isoprenaline-infused rabbits (ISO, 7 days mini-osmotic pump 100 micrograms/kg.h; n = 7) and saline-infused controls (SAL, n = 7). Failing human RV trabeculae were obtained at the time of cardiac transplantation. Failing rabbit trabeculae demonstrated increased baseline caffeine-induced contractures compared with controls, the response to cAMP was similar in the two groups (LIG 9.3 +/- 2.8 vs SH 10.6 +/- 3.2% Fmax; P = 0.55), There was no difference in the baseline SR Ca(2+)-loading in ISO trabeculae compared with SAL controls but there was a marked difference in the response to cAMP (11.1 +/- 5.4 vs 4.2 +/- 2.1% Fmax, P = 0.02). SR Ca(2+)-loading in failing human RV trabeculae was related to the severity of LV dysfunction (r = 0.59, P = 0.04) and demonstrated a marked cAMP-induced enhancement of caffeine-contracture (20.2 +/- 4.7% increase of Fmax) which was greater in patients with low compared with high ejection fraction. While beta-receptors are known to be down regulated in heart failure these results suggest that the scope for cAMP-mediated enhancement of SR Ca(2+)-loading is maintained.

Calcium uptake by cardiac sarcoplasmic reticulum (SR) is reported to be reduced in heart failure in the human and in a number of animal models. However, the majority of studies have examined end-stage heart failure in the human and few animal studies have taken account of the duration and severity of left ventricular dysfunction. In this study we have compared SR Ca2+ loading in a haemodynamically assessed, coronary artery ligation model of heart failure at 8 and 15 weeks after ligation. Trabeculae were isolated from the right ventricle and mounted for isometric tension measurement. They were treated with saponin to permeabilize the sarcolemma but retain SR function and bathed in a mock intracellular solution including adenosine triphosphate (ATP) and buffered Ca2+. Caffeine was used to release Ca2+ from the SR. The amplitude of the caffeine-induced contracture was used as a quantitative gauge of the Ca2+ content of the SR. Eight weeks after ligation, trabeculae demonstrated enhanced SR Ca2+ uptake as manifest by larger caffeine-induced contractures (e.g. 200 nM [Ca2+], 120 s loading - 38.2+/-9.2 versus 67.3+/-10.1% of maximum Ca2+-activated force, FCa, max, P=0.03). At 15 weeks, trabeculae from ligated hearts were not significantly different from controls with SR Ca2+ loading returning to control levels (e.g. 200 nM [Ca2+], 120 s loading - 47.3+/-9.6 versus 30.2+/-12.8% FCa, max, P=0.12). These data suggest that SR Ca2+ loading may increase in the early stages of heart failure and fall back to normal with an increasing duration of left ventricular dysfunction. Increased incidence of spontaneous Ca2+ release observed from the SR at 8 weeks and not at 15 weeks may represent an arrhythmogenic mechanism specific to the early phase of heart failure.

Doxorubicin is an anthracycline antibiotic that is used widely as a chemotherapeutic agent. However, the usefulness of this agent is limited due to its cardiotoxic effects. The mechanisms associated with this cardiotoxicity remain essentially unknown, despite numerous studies describing a range of structural and functional abnormalities. The purpose of the present study was to determine the in vivo and in vitro effects of doxorubicin exposure on sarcoplasmic reticulum (SR) Ca2+-content and contractile protein function. The Ca2+-content of SR is shown to have a biphasic response to in vivo and in vitro doxorubicin exposure that is time- and dose-dependent. In vitro doxorubicin exposure initially reduces the SR Ca2+-content, but the predominant action to block the SR Ca2+-release channel increases SR Ca2+-content within 60 min. Similar results are observed with in vivo doxorubicin exposure: it leads to Ca2+-overload. These data are consistent with the view that doxorubicin acts in a similar manner to ryanodine and results in cardiomyopathy due to Ca2+-overload.

Cardiac sarcoplasmic reticulum (SR) Ca(2+)-loading ability was assessed in a coronary artery ligation model of heart failure. Heart failure was produced in New Zealand White rabbits by ligation of the left marginal coronary artery. Sham-operated animals were used as controls. After hemodynamic and echocardiographic assessment 8 wk after coronary ligation, a free-running trabecula was isolated from the left or right ventricle, mounted for isometric tension measurement, and permeabilized with the chemical skinning agent saponin, leaving the SR functionally intact. The SR was Ca2+ loaded by exposure of the preparation to a mock intracellular solution with a Ca2+ concentration ([Ca2+]) of 150-300 nM. The amplitude of the caffeine-induced contracture was used as a measure of Ca2+ loaded by the SR. The same preparation was then treated with Triton X-100 to disrupt all cell membranes, and Ca2+ sensitivity {expressed as [Ca2+] required to produce 50% of maximal activation (pCa50)} of isometric tension production and maximum Ca2+ activated force (Cmax) were measured. Ligated animals demonstrated enhanced SR Ca(2+)-loading ability that correlated with the degree of left ventricular dysfunction. Enhanced SR Ca2+ loading was associated with evidence of SR Ca2+ overload revealed as spontaneous tension oscillations. Cmax and pCa50 were not significantly different from controls. Increased SR Ca(2+)-loading ability may predispose the SR to Ca2+ overload and could contribute to both contractile dysfunction and arrhythmogenesis in heart failure.

Objectives: Assessment of sarcoplasmic reticulum calcium-loading ability, myofilament force production and myofilament calcium sensitivity in ventricular trabeculae from patients with heart failure., Methods: Right ventricular trabeculae (diameter 150-250 microns) were obtained from 18 patients undergoing elective cardiac transplantation. These were mounted for isometric tension measurement and treated with saponin which permeabilises the sarcolemma leaving the sarcoplasmic reticulum (SR) functionally intact. The trabecula was bathed in a mock intracellular solution containing ATP and weakly buffered [Ca2+] at various concentrations (150-400 nM). The amplitude of caffeine-induced contractures was used as a quantitative measure of the SR calcium content and was correlated with the clinical severity of heart failure. The same trabecula was then exposed to a solution containing Triton-X100 (1%) which destroys all cell membranes leaving only the myofilaments intact. The maximum calcium-activated force (Cmax) and myofilament responsiveness to calcium was assessed., Results: Patients with ischaemic heart disease (IHD) and severe heart failure (PCWP > 20 mm Hg, ejection fraction < 15%, n = 8) demonstrated low SR Ca(2+)-loading ability compared with patients with IHD and moderate heart failure (PCWP-20 mmHg, LV ejection fraction > 20%, n = 6). Patients with dilated cardiomyopathy (DCM) (n = 4) demonstrated SR Ca(2+)-loading ability which was lower than either of the two IHD groups. Myofilament force production (per unit cross-sectional area) was not significantly different between the three groups. Myofilament responsiveness to Ca2+ demonstrated no relationship with severity of heart failure., Conclusions: In human heart failure, SR Ca(2+)-loading ability diminishes with increasing severity of heart failure. Myofilament force production and sensitivity to calcium are unaffected by severity of heart failure.

Oxygen-derived free radicals (FRs) and other reactive oxygen species (ROS) have been implicated in the deleterious aspects of myocardial infarction, neutrophil infiltration and post-ischaemic reperfusion. We studied their actions on the main intracellular organelles of Ca-compartmentation and force production (the sarcoplasmic reticulum (SR) and myofilaments) in rat heart preparations by using two forms of chemical 'skinning'. We recorded Ca(2+)-activated isometric tension or, in saponin-treated trabeculae where SR function is maintained, either tension alone or tension and [Ca2+] transients evoked by caffeine. A single, brief application of xanthine/xanthine oxidase (generating superoxide; O2-) rapidly and irreversibly inhibits Ca(2+)-activated force with a dose- and time-dependent action. The kinetics of residual force production are slowed. Rigor induction (by ATP withdrawal) before and during exposure to .O2- prevents this action, suggesting the .O2(-)-sensitive site is occluded in rigor. Myofilament Ca-sensitivity and SR function were unaffected by .O2- or physiologically relevant [H2O2] (< 10 microM). Briefly applying 10-50 microM hypochlorous acid (HOCl) increased Ca-sensitivity and resting tension, but reduced Ca-activated force, in a manner consistent with 'rigor-like' crossbridges being involved. HOCl also provoked spontaneous Ca-release but reduced net SR Ca-uptake. Electron microscopy reveals that the myofilament lattice suffers a characteristic disruption by HOCl but not by .O2-. We conclude that FRs and ROS associated with myocyte dysfunction, reperfusion and inflammation could contribute to post-ischaemic myocardial dysfunction.

Cardiac findings in adult endurance athletes are well characterized, but data regarding the "athlete's heart" in children are limited. This study evaluated cardiovascular features of 10 male prepubertal distance runners ages 11-13 years compared to 18 physically active but untrained boys. Mean VO2max values on treadmill testing for the two groups were 61.2 (3.2) and 51.1 (4.3) ml.kg-1.min-1, respectively. No significant differences in the frequency of carotid bruits, cervical venous hums, heart murmurs, or third and fourth heart sounds were observed between the groups. Mean resting heart rate was 71 (9) bpm for the runners and 73 (8) for the controls (p > 0.05). No significant differences were seen in EKG intervals, axes, or precordial voltages between runners and controls, and echocardiographic chamber sizes, wall thicknesses, and mass indexed to body surface area were also similar (p > 0.05). This study failed to identify clinical features of the "athlete's heart" in competitive child endurance runners compared to non-trained subjects.

Objective: The aim was to determine the effects of the superoxide anion, hydrogen peroxide, and hypochlorous acid on in situ cardiac sarcoplasmic reticulum., Methods: Simultaneous measurement of caffeine induced calcium release from the sarcoplasmic reticulum and subsequent myofilament tension generation was made on saponin permeabilised rat ventricular trabeculae before, during, and after exposure to various reactive oxygen species. The superoxide anion (O2.-) was generated using the xanthine-xanthine oxidase system, hypochlorous acid (HOCl) was prepared from NaOCl, and hydrogen peroxide (H2O2) was added from a 30% stock solution., Results: At [O2.-] sufficient to abolish tension generation by the myofilaments completely, the associated caffeine induced calcium release was unaffected. Both H2O2 and HOCl diminished caffeine induced calcium release but had differential effects on the associated tension response. Exposure to HOCl favoured the occurrence of spontaneous calcium releases from the sarcoplasmic reticulum., Conclusions: The reactive oxygen species H2O2 and HOCl reduced the amount of calcium release from the sarcoplasmic reticulum while O2.- was without effect. In some preparations it was observed that HOCl favoured spontaneous calcium release which might additionally reduce the calcium content of the sarcoplasmic reticulum.

Neutrophil activation occurs after myocardial infarction/ischaemia. They produce the reactive oxygen species (ROS) hypochlorous acid (HOCl) and hydrogen peroxide (H2O2) which could contribute to contractile dysfunction upon reperfusion. The myofilaments of 'skinned' rat cardiac muscle were exposed to ROS in various states of activation. Isometric force was measured at controlled degrees of activation. A single application of 10 microM HOCl for 1 min increased log [Ca2+] for half-maximal activation (log K1/2) from 5.23 to 5.32, initial maximum Ca-activated force (FCa, max) was reduced by 18.8 +/- 5.8% and resting tension increased to 15.4 +/- 8.0% of FCa, max. At 50 microM, a 1-min exposure to HOCl produced a greater increase in Ca-sensitivity (log K1/2 increased from 5.23 to 5.47), a greater reduction in FCa, max (falling by 42.3 +/- 23.2%) and a greater increase in resting tension (to 25 +/- 10.7% of FCa, max). The nature of the resting tension rise was examined by reducing pH before and during exposure to HOCl; the results are consistent with 'rigor-like' cross-bridges being involved. H2O2 was without effect on the myofilaments at physiologically relevant (< 10 microM) concentrations. These results suggest that ROS associated with inflammation could contribute to post-ischaemic myocardial dysfunction.

Among the mechanisms postulated to contribute to myocardial "stunning" is a depression of contractility by oxygen-derived free radicals. It has been suggested that these radicals might depress the calcium sensitivity of the contractile proteins. We have exposed the myofilaments (in chemically "skinned" rat cardiac muscle) to the superoxide anion and measured isometric force at controlled degrees of activation. Superoxide was generated by the xanthine/xanthine oxidase system: the effects to be described were shown to be specifically attributable to superoxide. Maximum calcium-activated force is reduced, or even completely abolished, in a dose-dependent fashion and without any alteration in calcium sensitivity. The myofilaments are highly sensitive to superoxide: significant force reduction has been shown to be caused by enzyme concentrations as low as 2 microunits/ml xanthine oxidase and with exposures of less than 1 minute to the generating system (at higher enzyme concentrations). Once force has been depressed, it cannot be recovered within the duration of the experiments described. When xanthine oxidase is applied during the calcium-induced contracture, tension falls steadily. However, a similar concentration is without immediate effect on the rigor contracture (evoked by applying ATP-free solutions). To account for the depression of maximum calcium-activated force, we conclude that some aspect of crossbridge behavior is particularly vulnerable to superoxide rather than that the radical has a nonspecific "proteolytic" effect. This action on the fundamental units of force production could contribute to myocardial stunning since the effects we report are consistent with many aspects of this phenomenon.