The effect of heat stress, dehydration and exercise on global left ventricular function and mechanics in healthy humans

This thesis examined the effect of heat stress, dehydration and exercise on global left ventricular (LV) function and LV twist, untwisting and strain (LV mechanics) in healthy individuals. The primary aim was to identify whether the different haemodynamics induced by heat stress, dehydration and exercise would be associated with alterations in systolic and diastolic LV mechanics as assessed by two-dimensional speckle tracking echocardiography. Study one showed that enhanced systolic and diastolic LV mechanics during progressively increasing heat stress at rest likely compensate in part for a lower venous return, resulting in a maintained stroke volume (SV). In contrast, heat stress during knee-extensor exercise did not significantly increase LV twist, suggesting that exercise attenuates the increase in LV mechanics seen during passive heat stress. Study two revealed that dehydration enhances systolic LV mechanics whilst diastolic mechanics remain unaltered at rest, despite pronounced reductions in preload. The maintenance of systolic and diastolic LV mechanics with dehydration during knee-extensor exercise further suggests that the large decline in SV with dehydration and hyperthermia is caused by peripheral cardiovascular factors and not impaired LV mechanics. During both, heat stress and dehydration, enhanced systolic mechanics were achieved solely by increases in basal rotation. In contrast, the third study demonstrated that when individuals are normothermic and euhydrated, systolic and diastolic basal and apical mechanics increase significantly during incremental exercise to approximately 50% peak power. The subsequent plateau suggests that LV mechanics reach their peak at sub-maximal exercise intensities. Together, the present findings emphasise the importance of acute adjustments in both, basal and apical LV mechanics, during periods of increased cardiovascular demand.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

The effect of heat stress, dehydration and exercise on global left ventricular function and mechanics in healthy humans

This thesis examined the effect of heat stress, dehydration and exercise on global left ventricular (LV) function and LV twist, untwisting and strain (LV mechanics) in healthy individuals. The primary aim was to identify whether the different haemodynamics induced by heat stress, dehydration and exercise would be associated with alterations in systolic and diastolic LV mechanics as assessed by two-dimensional speckle tracking echocardiography. Study one showed that enhanced systolic and diastolic LV mechanics during progressively increasing heat stress at rest likely compensate in part for a lower venous return, resulting in a maintained stroke volume (SV). In contrast, heat stress during knee-extensor exercise did not significantly increase LV twist, suggesting that exercise attenuates the increase in LV mechanics seen during passive heat stress. Study two revealed that dehydration enhances systolic LV mechanics whilst diastolic mechanics remain unaltered at rest, despite pronounced reductions in preload. The maintenance of systolic and diastolic LV mechanics with dehydration during knee-extensor exercise further suggests that the large decline in SV with dehydration and hyperthermia is caused by peripheral cardiovascular factors and not impaired LV mechanics. During both, heat stress and dehydration, enhanced systolic mechanics were achieved solely by increases in basal rotation. In contrast, the third study demonstrated that when individuals are normothermic and euhydrated, systolic and diastolic basal and apical mechanics increase significantly during incremental exercise to approximately 50% peak power. The subsequent plateau suggests that LV mechanics reach their peak at sub-maximal exercise intensities. Together, the present findings emphasise the importance of acute adjustments in both, basal and apical LV mechanics, during periods of increased cardiovascular demand.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Short report: Effect of exercise training on left ventricular mechanics after acute myocardial infarction-an exploratory study.

BACKGROUND: Cardiac rehabilitation (CR) exercise training is beneficial after myocardial infarction (MI). Whilst the peripheral adaptations to training are well defined, little is known regarding the effect on left ventricular (LV) remodelling, particularly LV function. Efficient LV ejection and filling is achieved through deformation and rotation of the myocardium in systole and diastole - LV mechanics. The response of LV mechanics to CR exercise training in MI patients is unknown. METHODS: In this observational exploratory study, 36 (of 40 enrolled) male, MI patients completed either 10-weeks of twice-weekly gym based cardiovascular exercise at 60-80% VO2peak(n=18), or a non-exercise control period (n=18). Cardiopulmonary exercise testing and speckle tracking echocardiography were performed at baseline and 10 weeks. RESULTS: Compared to the non-exercise group, VO2peakimproved with CR exercise training (Difference: +4.28 [95% CI: 1.34 to 7.23] ml.kg-1.min-1, P=0.01). Neither conventional LV structural or functional indices, nor LV global longitudinal strain, significantly changed in either group. In contrast, LV twist and twist velocity decreased in the exercise group and increased in the non-exercise group (Difference: -3.95° [95% CI: -7.92 to 0.03°], P=0.05 and -19.2°.s-1[95% CI: -35.9 to -2.7°.s-1], P=0.02, respectively). CONCLUSION: In MI patients who completed CR exercise training, LV twist and twist velocity decreased, whereas these parameters increased in patients who did not exercise. These preliminary data may indicate reverse LV functional remodelling and improved functional reserve. The assessment of LV twist may serve as an indicator of the therapeutic benefit of CR exercise training and should be investigated in larger trials

Segregation From Direction Differences in Dynamic Random-Dot Stimuli

Previous research has shown that a field of random dots in which each dot alternates between a slow and a fast speed, can give rise to the percept of two superimposed sheets of moving dots when the alternations are out of phase or asynchronous with each other [Vis. Res. 35 (1995) 1691]. Under those conditions, observers can discriminate changes in the slow speed independent of changes in the fast speed. The present study investigated whether such motion-based segregation could result when dots alternated between two different directions. Three observers viewed a variety of displays containing two directions of motion, one upward and one oblique, with the task of discriminating small trial-to-trial changes in the direction of the upward component. The oblique direction component also changed direction from trial-to-trial. The field of dots either alternated synchronously (all dots moved in the same direction and switched to the other direction simultaneously) or asynchronously. Results showed that when the dots alternated synchronously between the directions, observers’ direction discrimination performance was generally poor. However, when dots switched directions asynchronously, direction discrimination was only slightly elevated in comparison to that produced by a field of dots all moving in a single direction. Additional experiments demonstrated that this performance was not due to judging the global direction of the random-dot display. Thus the visual system had to segregate the stimulus into its component directions before integrating to arrive at the motion signal to be discriminated. It is concluded that for displays comprising elements that alternate between different directions, local direction signals can be used by the human visual system to effectively segregate a display so long as both direction signals are present simultaneously

APOBEC Mutational Signature and Tumor Mutational Burden as Predictors of Clinical Outcomes and Treatment Response in Patients With Advanced Urothelial Cancer

IntroductionTumor mutational burden (TMB) and APOBEC mutational signatures are potential prognostic markers in patients with advanced urothelial carcinoma (aUC). Their utility in predicting outcomes to specific therapies in aUC warrants additional study.MethodsWe retrospectively reviewed consecutive UC cases assessed with UCSF500, an institutional assay that uses hybrid capture enrichment of target DNA to interrogate 479 common cancer genes. Hypermutated tumors (HM), defined as having TMB ≥10 mutations/Mb, were also assessed for APOBEC mutational signatures, while non-HM (NHM) tumors were not assessed due to low TMB. The logrank test was used to determine if there were differences in overall survival (OS) and progression-free survival (PFS) among patient groups of interest.ResultsAmong 75 aUC patients who had UCSF500 testing, 46 patients were evaluable for TMB, of which 19 patients (41%) had HM tumors and the rest had NHM tumors (27 patients). An additional 29 patients had unknown TMB status. Among 19 HM patients, all 16 patients who were evaluable for analysis had APOBEC signatures. HM patients (N=19) were compared with NHM patients (N=27) and had improved OS from diagnosis (125.3 months vs 35.7 months, p=0.06) but inferior OS for patients treated with chemotherapy (7.0 months vs 13.1 months, p=0.04). Patients with APOBEC (N=16) were compared with remaining 56 patients, comprised of 27 NHM patients and 29 patients with unknown TMB, showing APOBEC patients to have improved OS from diagnosis (125.3 months vs 44.5 months, p=0.05) but inferior OS for patients treated with chemotherapy (7.0 months vs 13.1 months, p=0.05). Neither APOBEC nor HM status were associated with response to immunotherapy.ConclusionsIn a large, single-institution aUC cohort assessed with UCSF500, an institutional NGS panel, HM tumors were common and all such tumors that were evaluated for mutational signature analysis had APOBEC signatures. APOBEC signatures and high TMB were prognostic of improved OS from diagnosis and both analyses also predicted inferior outcomes with chemotherapy treatment