Preload maintenance protects against a depression in left ventricular systolic, but not diastolic, function immediately after ultraendurance exercise

This article has been made available through the Brunel Open Access Publishing Fund and is available from the specified link - Copyright © 2006 BMJ Publishing Group.Objective: To investigate indices of left ventricular (LV) function before and after a 224 km Ironman triathlon, specifically in the presence of unaltered haemodynamic loading. Method: LV loading and function were assessed before and after the race using M mode and Doppler echocardiography in 39 (mean (SD) age 33 (8) years, body mass 77.6 (8.6) kg; 36 male) triathletes in the Trendelenburg position. Specifically left ventricular end diastolic volume (LVEDV) was assessed to estimate preload, and systolic blood pressure to estimate afterload as well as heart rate (HR). Systolic functional indices included ejection fraction (EF) and the end systolic pressure/volume ratio (ESPV), and diastolic functional indices included peak mitral flow velocity in early (E) and atrial (A) filling as well as the ratio E/A. Data obtained before and after the race were compared by t tests, and delta LV functional indices were correlated with delta heart rate. Results: Preload (LVEDV: 143 (34) ml before v 147 (34) ml after) and afterload (systolic blood pressure 121 (13) v 115 (20) mm Hg) were not significantly altered after the race (p>0.05), nor were EF (61 (8)% v 58 (10)%) and ESPV (2.4 (0.9) v 2.1 (0.8) mm Hg/cm3). The diastolic filling ratio E/A was significantly reduced after the race (1.73 (0.25) v 1.54 (0.23); p0.05). Conclusion: When preload and afterload are unaltered after the race, because of the adoption of a unique assessment posture, LV systolic function is not depressed. A depression in LV diastolic function persists which is not explained by an increase in heart rate after the race

Process simulation based decisional tool to evaluate strategies for continuous downstream bioprocess implementation - A CDMO perspective

To maintain a competitive space in the rapidly expanding and highly competitive market, many biopharmaceutical companies are outsourcing to contract development and manufacturing organizations (CDMOs) to accelerate research and development, shorten the time to market, alleviate internal capacity and technical constraints, and reduce risks associated with production [1]. To acquire new and maintain current clients, CDMOs must have strong, diverse technical offerings for development, manufacture, and testing of products with competitive pricing and timelines [2]. Adopting innovative technologies like continuous downstream processing can help debottleneck the process and reduce processing time, which is the most appealing to CDMOs as it translates to an increased number of batches per year. The majority of continuous processing assessments to date have focused on cost of goods and not on the time reduction potential [3-7]. End-to-end continuous downstream processing is not always practical as CDMOs must accommodate a wide range of molecules and processes. Hence, it is imperative to evaluate and customize continuous production based on client needs. Application of process simulation as a decisional tool to select an appropriate downstream processing strategy was evaluated. Two modelling programs were evaluated: BioSolve Process and SuperPro Designer®. Fully continuous and hybrid (continuous Protein A operation only) downstream processing were assessed for a 2000 L fed-batch bioreactor producing 1, 5, and 10 g/L of monoclonal antibody at 40 and 200 kg production demands. Hybrid and continuous processing decreased batch duration by 20% and 60%, respectively. Continuous processing was more favorable for higher titer processes (≥ 5 g/L). The largest cost reductions were observed for 5 and 10 g/L titer processes during 40 kg production. The results highlight the business case for continuous downstream bioprocessing especially at a CDMO. Selection of a processing method will be influenced by a range of factors and the impact can easily be assessed using process simulation. Therefore, it is recommended that CDMOs use process simulation to ensure the most favorable processing strategy is selected. [1] O. Gassmann, A. Schuhmacher, M. von Zedtwitz, G. Reepmeyer, The Make-or-Buy Challenge: How to In-and Outsource Innovation, Leading Pharmaceutical Innovation, Springer2018, pp. 79-110. [2] R. Hernandez, Contract Biomanufacturing Firms Become More Specialized, BioPharm International, 28 (2015) 22-27. [3] D. Pollard, M. Brower, Y. Abe, A.G. Lopes, Standardized Economic Cost Modeling for Next-Generation MAb Production, BioProcess Int, (2016). [4] A. Xenopoulos, A new, integrated, continuous purification process template for monoclonal antibodies: process modeling and cost of goods studies, Journal of biotechnology, 213 (2015) 42-53. [5] J. Hummel, M. Pagkaliwangan, X. Gjoka, T. Davidovits, R. Stock, T. Ransohoff, R. Gantier, M. Schofield, Modeling the Downstream Processing of Monoclonal Antibodies Reveals Cost Advantages for Continuous Methods for a Broad Range of Manufacturing Scales, Biotechnology journal, (2018) 1700665. [6] J. Pollock, J. Coffman, S.V. Ho, S.S. Farid, Integrated continuous bioprocessing: Economic, operational, and environmental feasibility for clinical and commercial antibody manufacture, Biotechnology progress, 33 (2017) 854-866. [7] S. Klutz, L. Holtmann, M. Lobedann, G. Schembecker, Cost evaluation of antibody production processes in different operation modes, Chemical Engineering Science, 141 (2016) 63-74

Randomised feasibility trial into the effects of low-frequency electrical muscle stimulation in advanced heart failure patients.

OBJECTIVES: Low-frequency electrical muscle stimulation (LF-EMS) may have the potential to reduce breathlessness and increase exercise capacity in the chronic heart failure population who struggle to adhere to conventional exercise. The study's aim was to establish if a randomised controlled trial of LF-EMS was feasible. DESIGN AND SETTING: Double blind (participants, outcome assessors), randomised study in a secondary care outpatient cardiac rehabilitation programme. PARTICIPANTS: Patients with severe heart failure (New York Heart Association class III-IV) having left ventricular ejection fraction <40% documented by echocardiography were eligible. INTERVENTIONS: Participants were randomised (remotely by computer) to 8 weeks (5×60 mins per week) of either LF-EMS intervention (4 Hz, continuous, n=30) or sham placebo (skin level stimulation only, n=30) of the quadriceps and hamstrings muscles. Participants used the LF-EMS straps at home and were supervised weekly OUTCOME MEASURES: Recruitment, adherence and tolerability to the intervention were measured during the trial as well as physiological outcomes (primary outcome: 6 min walk, secondary outcomes: quadriceps strength, quality of life and physical activity). RESULTS: Sixty of 171 eligible participants (35.08%) were recruited to the trial. 12 (20%) of the 60 patients (4 LF-EMS and 8 sham) withdrew. Forty-one patients (68.3%), adhered to the protocol for at least 70% of the sessions. The physiological measures indicated no significant differences between groups in 6 min walk distance(p=0.13) and quality of life (p=0.55) although both outcomes improved more with LF-EMS. CONCLUSION: Patients with severe heart failure can be recruited to and tolerate LF-EMS studies. A larger randomised controlled trial (RCT) in the advanced heart failure population is technically feasible, although adherence to follow-up would be challenging. The preliminary improvements in exercise capacity and quality of life were minimal and this should be considered if planning a larger trial. TRIAL REGISTRATION NUMBER: ISRCTN16749049

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

Reduced left ventricular filling following blood volume extraction does not result in compensatory augmentation of cardiac mechanics.

An acute non-invasive reduction in preload has been shown to augment cardiac mechanics to maintain stroke volume and cardiac output. Such interventions induce concomitant changes in heart rate (HR), whereas blood volume extraction reduces preload without HR changes. Therefore, the purpose of this study was to determine whether a preload reduction in isolation resulted in augmented stroke volume achieved via enhanced cardiac mechanics. Nine healthy volunteers (4 female, age 29 ± 11 years) underwent echocardiography for the assessment of left ventricular (LV) volumes and mechanics in a supine position at baseline and end-extraction following the controlled removal of 25% of total blood volume (1062 ± 342 ml). Arterial blood pressure was monitored continuously by a pressure transducer attached to an indwelling radial artery catheter. HR and total peripheral resistance were unchanged from baseline to end extraction, but systolic blood pressure was reduced (148 to 127 mmHg). LV end diastolic volume (89 to 71 ml) and stroke volume (56 to 37 ml) were significantly reduced from baseline to end extraction; however, there was no change in LV twist, basal or apical rotation. In contrast, LV longitudinal strain (-20 to -17%) and basal circumferential strain (-22 to -19%) were significantly reduced from baseline to end extraction. In conclusion, a preload reduction during blood volume extraction does not result in compensatory changes in stroke volume or cardiac mechanics. Our data suggest that LV strain is dependent on LV filling and consequent geometry whereas LV twist could be mediated by heart rate. This article is protected by copyright. All rights reserved

Age-related differences in left ventricular structure and function between healthy men and women

Full Article Figures & data References Supplemental Citations Metrics Reprints & Permissions Get access Abstract Objectives: Cardiovascular function generally decreases with age, but whether this decrease differs between men and women is unclear. Our aims were twofold: (1) to investigate age-related sex differences in left ventricular (LV) structure, function and mechanics, and (2) to compare these measures between pre- and postmenopausal women in the middle-aged group. Methods: Resting echocardiography was performed in a cross-sectional sample of 82 healthy adults (14 young men, 19 middle-aged men, 15 young women, 34 middle-aged women: 15 premenopausal and 19 postmenopausal). Two-way ANOVAs were used to examine sex × age interactions, and t-tests to compare pre- and postmenopausal women (α < 0.1). Results: Normalized LV mass, stroke volume and end-diastolic volume were significantly lower in middle-aged than young men, but this difference was smaller between middle-aged and young women. Peak systolic apical mechanics were significantly greater in middle-aged men than in middle-aged women, but not between young men and women. Postmenopausal women had significantly lower LV relaxation and mechanics (torsion, twisting velocity and apical circumferential strain rates) compared with middle-aged premenopausal women. Conclusion: Our cross-sectional findings suggest that the hearts of men and women may age differently, with men displaying greater differences in LV volumes accompanied by differences in apical mechanics

The impact of chronic endurance and resistance training upon the right ventricular phenotype in male athletes

Objectives The traditional view of differential left ventricular adaptation to training type has been questioned. Right ventricular (RV) data in athletes are emerging but whether training type mediates this is not clear. The primary aim of this study was to evaluate the RV phenotype in endurance- vs. resistance-trained male athletes. Secondary aims included comparison of RV function in all groups using myocardial speckle tracking, and the impact of allometric scaling on RV data interpretation. Methods A prospective cross-sectional design assessed RV structure and function in 19 endurance-trained (ET), 21 resistance-trained (RT) and 21 sedentary control subjects (CT). Standard 2D tissue Doppler imaging and speckle tracking echocardiography assessed RV structure and function. Indexing of RV structural parameters to body surface area (BSA) was undertaken using allometric scaling. Results A higher absolute RV diastolic area was observed in ET (mean ± SD: 27 ± 4 cm2) compared to CT (22 ± 4 cm2; P < 0.05) that was maintained after scaling. Whilst absolute RV longitudinal dimension was greater in ET (88 ± 9 mm) than CT (81 ± 10 mm; P < 0.05), this difference was removed after scaling. Wall thickness was not different between ET and RT and there were no between group differences in global or regional RV function. Conclusion We present some evidence of RV adaptation to chronic ET in male athletes but limited structural characteristics of an athletic heart were observed in RT. Global and regional RV functions were comparable between groups. Allometric scaling altered data interpretation in some variables