An investigation into the effect of skeletal muscle metabolic function & cardio-respiratory fitness on exercise capacity in the presence and absence of disease

It is uncommon for cardio-respiratory fitness and skeletal muscle metabolic function to be assessed independently within an exercise test. Exercise capacity may require adaptation of one or other of these systems to a greater or lesser extent and the presence of disease may affect them to different extents. The physiological mechanisms underpinning the decline in exercise tolerance with age/disease and the benefits of exercise-training as a preventative therapy for some diseases are not fully understood. In this thesis functional capacity was assessed in terms of oxidative capacity. Near-Infrared Spectroscopy (NIRS) measures microvascular changes in oxygenated and deoxygenated haemoglobin and can be used to estimate oxidative capacity in skeletal muscle when combined with arterial occlusions. Oxidative capacity of skeletal muscle was determined as part of 3 studies; (1) in a group of older adults (>65 years old) with or without type 2 diabetes (T2D), (2) in a tri-ethnic group of older adults from the same cohort with the objective of determining ethnic difference in oxidative capacity independently of T2D and (3) in a group of young adults before and after a period of endurance training in preparation for their first marathon. NIRS measurements of muscle oxidative capacity revealed poorer function in older adults with diabetes (57.5±6.8 versus 38.7±2.6 s, p=0.02) and poorer oxidative capacity in South Asian older adults independently of T2D (difference (95%CI): 10.1 (2.3, 17.9) s, p=0.011). In young healthy men and women, skeletal muscle oxygen consumption post-exercise increased with endurance training (p<0.01) despite no improvement in cardio-pulmonary peakV̇O2 (p=0.81). Faster marathon completion time correlated with cardio-pulmonary peakV̇O2 (rpartial=-0.55, p< 0.01) but not oxidative capacity. Skeletal muscle oxidative capacity can be measured in old and young adults using NIRS combined with arterial occlusion performed immediately following exercise testing. People with T2D have poorer oxidative capacity compared to people without and South Asians have poorer oxidative capacity compared to Europeans which African Caribbean’s and Europeans had similar skeletal muscle oxidative capacity. Skeletal muscle metabolic adaptions occur following 6 months of endurance training. Although the cardio-pulmonary system is limiting for running performance, skeletal muscle changes can be detected despite no significant improvement in cardio-pulmonary function

A validation study of two wrist worn wearable devices for remote assessment of exercise capacity

We determined wearable device errors in assessing a 6- Minute Walk Test (6MWT). 16 healthy adults (male 7(44%), mean age±SD 27±4 years) performed a standard (6MWT-S) and modified, ‘free range’, (6MWT-FR) protocols with a Garmin and Fitbit smartwatch to measure three parameters: distance, step count and heart rate (HR). Distance during the 6MWT-FR was measured with smaller errors during 6MWT-S for both Garmin (Mean Absolute Percentage Error, MAPE=9.8% [4.6%,12.6%] vs 18.5%[13.0%,27.4%], p<0.001) and Fitbit (MAPE=9.4%[4.5%,13.3%] vs 22.7%[18.3%,29.3%], p<0.001). Steps were measured with smaller errors with Garmin (MAPE=2.3%[1.1%,2.9%]; r=0.96) than Fitbit (Fitbit: MAPE=8.1%[5.0%,12.9%]; r=0.24). Heart rate at rest, peak exercise and recovery was measured with median MAPE ranging between 1.2% and 2.9%, with no evidence of difference between the two devices. Wearable measurements of the 6MWT provide insights about exercise capacity which could be monitored and evaluated remotely

Spectroscopic Confirmation of a z=2.79 Multiply Imaged Luminous Infrared Galaxy Behind the Bullet Cluster

We report spectroscopic confirmation and high-resolution infrared imaging of a z=2.79 triply-imaged galaxy behind the Bullet Cluster. This source, a Spitzer-selected luminous infrared galaxy (LIRG), is confirmed via polycyclic aromatic hydrocarbon (PAH) features using the Spitzer Infrared Spectrograph (IRS) and resolved with HST WFC3 imaging. In this galaxy, which with a stellar mass of M*=4e9 Msun is one of the two least massive ones studied with IRS at z>2, we also detect H_2 S(4) and H_2 S(5) pure rotational lines (at 3.1 sigma and 2.1 sigma) - the first detection of these molecular hydrogen lines in a high-redshift galaxy. From the molecular hydrogen lines we infer an excitation temperature T=377+68-84 K. The detection of these lines indicates that the warm molecular gas mass is 6(+36-4)% of the stellar mass and implies the likely existence of a substantial reservoir of cold molecular gas in the galaxy. Future spectral observations at longer wavelengths with facilities like the Herschel Space Observatory, the Large Millimeter Telescope, and the Atacama Pathfinder EXperiment (APEX) thus hold the promise of precisely determining the total molecular gas mass. Given the redshift, and using refined astrometric positions from the high resolution imaging, we also update the magnification estimate and derived fundamental physical properties of this system. The previously published values for total infrared luminosity, star formation rate, and dust temperature are confirmed modulo the revised magnification; however we find that PAH emission is roughly a factor of five stronger than would be predicted by the relations between the total infrared and PAH luminosity reported for SMGs and starbursts in Pope et al. (2008).Comment: 8 pages, 4 figures, accepted to Ap

Skeletal Muscle Tissue Saturation Changes Measured Using Near Infrared Spectroscopy During Exercise Are Associated With Post-Occlusive Reactive Hyperaemia

Measuring local haemodynamics in skeletal muscle has the potential to provide valuable insight into the oxygen delivery to tissue, especially during high demand situations such as exercise. The aim of this study was to compare the skeletal muscle microvascular response during post-occlusive reactive hyperaemia (PORH) with the response to exercise, each measured using near-infrared spectroscopy (NIRS) and to establish if associations exist between muscle measures and exercise capacity or sex. Participants were from a population-based cohort study, the Southall and Brent Revisited (SABRE) study. Skeletal muscle measures included changes in tissue saturation index at the onset of exercise (∆TSIBL-INC) and across the whole of exercise (∆TSIBL-EE), time to 50%, 95% and 100% PORH, rate of PORH recovery, area under the curve (AUC) and total oxygenated Haemoglobin (oxy-Hb) change during PORH. Exercise capacity was measured using a 6-min stepper test (6MST). Analysis was by multiple linear regression. In total, 558 participants completed the 6MST with NIRS measures of TSI (mean age±SD: 73 ± 7years, 59% male). A sub-set of 149 participants also undertook the arterial occlusion. Time to 100% PORH, recovery rate, AUC and ∆oxy-Hb were all associated with ∆TSIBL-EE (β-coefficient (95%CI): 0.05 (0.01, 0.09), p = 0.012; -47 (-85, -9.9), p = 0.014; 1.7 (0.62, 2.8), p = 0.002; 0.04 (0.002.0.108), p = 0.041, respectively). Time to 95% & 100% PORH, AUC and ∆oxy-Hb were all associated with ∆TSIBL-INC (β-coefficient (95%CI): -0.07 (-0.12,-0.02), p = 0.02; -0.03 (-0.05, -0.003), p = 0.028; 0.85 (0.18, 1.5), p = 0.013 & 0.05 (0.02, 0.09), p = 0.001, respectively). AUC and ∆Oxy-Hb were associated with steps achieved (β-coefficient (95%CI): 18.0 (2.3, 33.7), p = 0.025; 0.86 (0.10, 1.6), p = 0.027). ∆TSIBL-EE was associated with steps and highest VO2 (1.7 (0.49, 2.9), p = 0.006; 7.7 (3.2, 12.3), p = 0.001). ∆TSIBL-INC was associated with steps and VO2 but this difference was attenuated towards the null after adjustment for age, sex and ethnicity. ∆TSIBL-EE was greater in women (3.4 (0.4, 8.9) versus 2.1 (0.3, 7.4), p = 0.017) and ∆TSIBL-INC was lower in women versus men (2.4 (0.2, 10.2) versus 3.2 (0.2, 18.2), p = 0.016). These Local microvascular NIRS-measures are associated with exercise capacity in older adults and several measures can detect differences in microvascular reactivity between a community-based sample of men and women

Does 3D-speckle tracking echocardiography improve prediction of major cardiovascular events in a multi-ethnic general population? A Southall and Brent Revisited (SABRE) cohort study

3D-speckle tracking echocardiography(3D-STE) allows simultaneous assessment of ejection fraction(EF) and multidirectional strains, but its prognostic utility in the general population is unknown. We investigated if 3D-STE strains predicted a composite of major cardiac endpoints(MACE) beyond cardiovascular risk factors(CVDRF), and whether they were superior to 3D-EF. 529 participants in SABRE, a UK-based tri-ethnic general population cohort (69±6y; 76.6% male) with acceptable 3D-STE imaging were studied. Associations between 3D-EF or multidirectional myocardial strains and MACE(coronary heart disease(fatal/non-fatal), heart failure hospitalization, new-onset arrhythmia and cardiovascular mortality) were determined using Cox regression including adjustment for CVDRF and 2D-EF. Whether 3D-EF, global longitudinal strain(3D-GLS) and principle tangential strain(3D-PTS/3D-strain) improved cardiovascular risk stratification over CVDRF was investigated using a likelihood ratio test on a series of nested Cox proportional hazards models and Harrell's C statistics. During follow-up(median, 12y), there were 92 events. 3D-EF, 3D-GLS and 3D-PTS and 3D-RS were associated with MACE in unadjusted and models adjusted for CVDRF but not CVDRF+2D-EF. Compared to 3D-EF, both 3D-GLS and 3D-PTS slightly improved the predictive value over CVDRF for MACE, but the improvement was modest(C statistic increased from 0.698(0.647, 0.749) to 0.715(0.663, 0.766) comparing CVDRF with CVDRF +3D-GLS). 3D-STE-derived LV myocardial strains predicted MACE in a multi-ethnic general population sample of elderly individuals from the UK; however the added prognostic value of 3D-STE myocardial strains was small

Associations of carotid atherosclerosis with cognitive function and brain health: Findings from a UK tri-ethnic cohort study (Southall and Brent Revisited)

BACKGROUND: Cognitive function has an important role in determining the quality of life of older adults. Cardiovascular disease (CVD) is common in older people and may compromise cognitive performance; however, the extent to which this is related to carotid atherosclerosis is unclear. AIM: We investigated associations between carotid atherosclerosis and cognitive function and neuroimaging markers of brain health in a UK multi-ethnic community-based sample including older people of European, South Asian, and African-Caribbean ethnicity. METHODS: Carotid plaques and intima-media thickness (cIMT) were assessed using ultrasound in 985 people (mean age 73.2y, 56 % male). Associations of carotid atherosclerosis with cognitive function (memory, executive function, language and CSI-D, a global measure of cognitive state) and neuroimaging measures (total brain volume, hippocampal volume, white matter (WM) lesion volume and coalescence score) were analysed using regression analyses, with and without adjustment for potential confounders using two models: 1) adjustment for age, sex, and ethnicity; 2) model 1 plus education, physical activity category, body mass index, hypertension, diabetes, total and high density lipoprotein cholesterol, atrial fibrillation, smoking, previous CVD, alcohol consumption, and presence of chronic kidney disease. RESULTS: People with carotid plaque or higher cIMT had lower CSI-D score, poorer memory poorer executive function and higher WM lesion volume and coalescence. Language was poorer in people with plaque but was not correlated with cIMT. Associations with plaque were preserved after full adjustment (model 2) but relationships for cIMT were attenuated. Associations with other plaque characteristics were generally unconvincing after adjustment. CONCLUSIONS: This multi-ethnic cohort study provides evidence that presence of carotid plaque, is associated with poorer cognitive function and brain health

Sex-differences in associations of LV structure and function measured by echocardiography with long-term risk of mortality and cardiovascular morbidity

BACKGROUND: Three-dimensional echocardiography (3DE) measures of the left ventricle (LV) predict outcomes in high risk individuals, but their prognostic value in the general population is unknown. We aimed to establish whether 3DE was associated with mortality and morbidity in a multi-ethnic community-based sample, if associations differed by sex, and explored potential mechanisms explaining sex differences. METHODS: 922 individuals (69.7 ± 6.2 years; 717 men) from the SABRE study underwent a health examination including echocardiography. Associations between 3DE LV measures (ejection fraction (EF), end-diastolic volume (EDV), end-systolic volume (ESV), LV remodeling index (LVRI) and LV sphericity index (LVSI), and all-cause mortality and a composite cardiovascular endpoint [comprising new onset (non)fatal coronary heart disease, heart failure hospitalization, new-onset arrhythmias and cardiovascular mortality] were determined using multivariable Cox regression over a median follow-up of 8 years (all-cause mortality) and 7 years (composite cardiovascular endpoint). RESULTS: There were 123 deaths and 151 composite cardiovascular endpoints. Lower EF, higher LV volumes and LVSI were associated with increased all-cause mortality, and higher LV volumes were associated with the composite cardiovascular endpoint independent of potential confounders. Associations between LV volumes, LVRI, LVSI, and mortality differed by sex (p interaction <0.1). In men increased LV volumes and LVSI and decreased LVRI and EF were associated with higher mortality, but associations were null or reversed in women (hazard ratios (95% CI) men vs. women: EDV 1.25 (1.05, 1.48) vs. 0.54 (0.26, 1.10); ESV, 1.36 (1.12, 1.63) vs. 0.59 (0.33, 1.04); LVRI, 0.79 (0.64, 0.96) vs. 1.70 (1.03, 2.80); LVSI, 1.27 (1.05, 1.54) vs. 0.61 (0.32, 1.15); and EF, 0.78 (0.66, 0.93) vs. 1.27 (0.69, 2.33). Similar sex differences were observed for associations with the composite cardiovascular outcome. Adjustment for LV diastolic stiffness and arterial stiffness marginally attenuated these differences. CONCLUSIONS: 3DE measures of LV volume and remodeling are associated with all-cause mortality and cardiovascular morbidity; however, some associations differ by sex. Sex-differences in LV remodeling patterns may influence mortality and morbidity risk in the general population

Recreational marathon running does not cause exercise-induced left ventricular hypertrabeculation.

BACKGROUND: Marathon running in novices represents a natural experiment of short-term cardiovascular remodeling in response to running training. We examine whether this stimulus can produce exercise-induced left ventricular (LV) trabeculation. METHODS: Sixty-eight novice marathon runners aged 29.5 ± 3.2 years had indices of LV trabeculation measured by echocardiography and cardiac magnetic resonance imaging 6 months before and 2 weeks after the 2016 London Marathon race, in a prospective longitudinal study. RESULTS: After 17 weeks unsupervised marathon training, indices of LV trabeculation were essentially unchanged. Despite satisfactory inter-observer agreement in most methods of trabeculation measurement, criteria defining abnormally hypertrabeculated cases were discordant with each other. LV hypertrabeculation was a frequent finding in young, healthy individuals with no subject demonstrating clear evidence of a cardiomyopathy. CONCLUSION: Training for a first marathon does not induce LV trabeculation. It remains unclear whether prolonged, high-dose exercise can create de novo trabeculation or expose concealed trabeculation. Applying cut off values from published LV noncompaction cardiomyopathy criteria to young, healthy individuals risks over-diagnosis

The Emission Line Properties of Gravitationally-lensed 1.5 < z < 5 Galaxies

We present and analyse near-infrared spectroscopy for a sample of 28 gravitationally- lensed star-forming galaxies in the redshift range 1.5 < z < 5, observed mostly with the Keck II telescope. With typical magnifications of ~1.5-4 magnitudes, our survey provides a valuable census of star formation rates, gas-phase metallicities and dynamical masses for a representative sample of low luminosity galaxies seen at a formative period in cosmic history. We find less evolution in the mass-metallicity relation compared to earlier work that focused on more luminous systems with z - 2-3, especially in the low mass (- 10^9 Msol) where our sample is - 0.25 dex more metal-rich. We interpret this offset as a result of the lower star formation rates (typically a factor of -10 lower) for a given stellar mass in our sub-luminous systems. Taking this effect into account, we conclude our objects are consistent with a fundamental metallicity relation recently proposed from unlensed observations.Comment: 22 pages, 12 figures, MNRAS, version including proof correction

Elevated Blood Pressure in Adolescence Is Attributable to a Combination of Elevated Cardiac Output and Total Peripheral Resistance:Evidence Against a Hyperkinetic State

Unlike in older people, it has been suggested that elevated blood pressure (BP) in young people is because of high cardiac output accompanied by normal total peripheral resistance (TPR)-a hyperkinetic/hyperdynamic circulation. We investigated this in a large, United Kingdom-based birth cohort of adolescents. The study was conducted on 2091 17-year-old participants in the ALSPAC (Avon Longitudinal Study of Parents and Children)-a prospective population-based birth cohort study. BP measurement and echocardiography were performed, and heart rate (HR), stroke volume (SV), and TPR were calculated. Data are means (SD). Higher quintiles of systolic BP were associated with higher SV, higher HR, and higher TPR. The proportional contribution made by SV, HR, and TPR to mean arterial pressure differed little by systolic BP quintile (SV [32%-34%], HR [25%-29%], and TPR [39%-41%]). Higher BP is attributable to a combination of higher cardiac output (ie, SV×HR) and higher TPR in a population-based sample of adolescents. There is no evidence of a disproportionate contribution from elevated cardiac output at higher BP levels