Neuromuscular Fatigability in Individuals With Heart Failure

Background:

Exercise intolerance is a hallmark symptom of chronic heart failure with reduced ejection fraction (HFrEF) and is associated with reduced quality of life as well as being a strong prognostic indicator. Research in recent years has attempted to better understand the aetiology of exercise intolerance to provide therapeutic targets to improve physical capacity and quality of life, with studies primarily focusing on maximal oxygen uptake, metabolic thresholds and oxygen uptake kinetics. Another important determinant of exercise intolerance is neuromuscular fatigability, defined as the reduction in neuromuscular function measured after exercise of a discrete time period. At present, the few studies that have assessed neuromuscular fatigability in individuals with HFrEF have utilised exercise involving a small muscle mass, such as isometric knee extension. However, one limitation of this approach is that it does not reflect the types of activity performed on a daily basis, and thereby lacks ecological validity. Specifically, activities of daily living (e.g. walking, gardening, housework or climbing stairs) involve dynamic, large muscle mass exercise and in turn a substantially higher cardiorespiratory demand relative to isometric tasks. At present, there is limited research assessing neuromuscular fatigability in individuals with HFrEF during large muscle mass exercise. Research characterising fatigability and determining its underlying mechanisms can help better understand the aetiology of exercise intolerance, and in turn provide therapeutic targets aimed at improving physical capacity and quality of life in individuals with HFrEF.

Neuromuscular fatigability is tightly linked with oxygen transport, with impairments in oxygen transport associated with a higher reliance on anaerobic metabolism and the production of contractile function-impairing metabolites. Given that HFrEF is associated with impairments at multiple steps along the oxygen cascade, limitations in oxygen transport likely represent an important contributor to neuromuscular fatigability in individuals with HFrEF. In turn, the loci of limitations in oxygen transport can be broadly categorised as being of central (cardiac and/or pulmonary) and peripheral origin (vascular and muscle mitochondrial). While those with HFrEF may exhibit higher neuromuscular fatigability as a result of both central and peripheral impairments, the relative importance of each is uncertain. An experimental model which has previously been used to provide insight into central and peripheral determinants of neuromuscular fatigability is through the manipulation of active muscle mass during exercise. Performing exercise with a smaller muscle mass, such as during single-leg cycling (SLC), allows a cardiac and pulmonary reserve to become available, meaning that cardiac and pulmonary constraints to exercise tolerance are attenuated. The lower cardiopulmonary constrains on leg blood flow and oxygen delivery in SLC will therefore permit the assessment of neuromuscular fatigability with a lower influence of central limitations. In contrast, when exercising with a large muscle mass, such as during double-leg cycling (DLC), there is a greater oxygen demand as a larger proportion of the total bodily muscle mass is active. As such, the contribution of impaired cardiac output in individuals with HFrEF becomes of greater relative importance during large muscle mass exercise. Moreover, the increased demand of respiration during large muscle mass exercise requires greater redistribution of blood and oxygen centrally, away from the exercising muscles. Comparing responses to SLC and DLC can therefore provide insight into the relative contribution of central and peripheral limitations to neuromuscular fatigue and exercise intolerance in those with HFrEF.

One potential strategy to attenuate fatigability is through nitrate supplementation (i.e. beetroot juice). Specifically, the consumption of nitrate-rich beetroot juice promotes increased nitric oxide bioavailability, which in turn can enhance local perfusion and oxygenation, skeletal muscle contractility, and muscle efficiency. Given that individuals with CHF have impaired nitric oxide bioavailability and reduced local perfusion and oxygenation, which likely contribute to impaired fatigability, nitric oxide represents an attractive intervention to mitigate fatigability and improve exercise tolerance. To date, no study has assessed the effect of nitrate supplementation on neuromuscular fatigability in individuals with CHF.

Aims:

The aims of this project are to 1) characterise muscle fatigue in individuals with chronic heart failure during exercise involving a smaller and larger muscle mass (Part I), 2) to determine the effect of nitrate supplementation on muscle fatigue during large muscle mass exercise in individuals with chronic heart failure (Part II), 3) understand the impact of exercise intolerance on quality of life in individuals with chronic heart failure (Part III).

Study design:

Part I is a cross-sectional, observational study, which will characterise neuromuscular fatigability in individuals with HFrEF during DLC and SLC. On seperate visits and in a randomised order, participants will perform incremental SLC and DLC to exhaustion, with cycling interspersed with measures of neuromuscular function. Part II is a randomised crossover interventional study, which will assess neuromuscular fatigability following nitrate supplementation and a placebo-control in individuals with HFrEF during DLC. For part II, participants will consume nitrate-rich beetroot juice in the lead up to one visit, and beetroot juice with nitrate extracted as a placebo-control in the lead up to another visit, with the order of the conditions randomised. Part III is a qualitative study, which will evaluate the impact of exercise intolerance on quality of life in individuals with HFrEF through semi-structured interviews and questionnaires. All participants will complete both Parts I and II of the study, while Part III is optional (i.e. participants will be able to participate in Parts II and II if they choose not to take part in Part III).

Recruitment procedures:

Patients will be identified from the Heart Failure Clinic run at the Royal Victoria Infirmary and Freeman Hospital, Newcastle upon Tyne, by Consultant Cardiologists. The consultant cardiologist will then invite the patient to talk to a member of the research team. This will take place at the end of the patient's consultation, after which a member of the research team will meet the patient to explain the study. If the patient is interested, they will be provided with an information sheet. To avoid coercion, the patient will not be asked to make a decision in the presence of a member of the research team, and instead will be afforded 48 hours to read the information sheet and decide whether they would like to participate. The research team will request to call the patient after this 48 hour period to discuss the study and answer any questions. If the patient is happy to proceed when they will be invited to the Clinical Research Facility for Visit 1, where they will provide informed consent if they are willing to become a participant in the study.

Research visits - Parts I and II - Quantitative work package:

Individuals with HFrEF (n = 28) will visit the NIHR Clinical Research Facility on 4 occasions across Parts I and II of the study. Visit 1 will involve screening and consent, completion of questionnaires, familiarisation with study procedures, and performing a non-invasive measurement of mitochondrial function using near-infrared spectroscopy (NIRS). Visits 2-4 will be randomised in order, and will include, 1) incremental single-leg cycling to exhaustion with intermittent assessments of neuromuscular function, 2) incremental double-leg cycling to exhaustion with intermittent assessments of neuromuscular function, following a period of supplementation with nitrate-rich beetroot juice and, 3) incremental double-leg cycling to exhaustion with intermittent assessments of neuromuscular function, following a period of supplementation with a nitrate-extracted beetroot juice placebo.

Part III - Qualitative work package:

While Parts I and II will further our understanding on the aetiology of exercise intolerance and the effect of nitrate supplementation in improving exercise tolerance in individuals with CHF, it is important to clarify the impact of exercise intolerance on the lives of these individuals. As such, the aim of Part III is to understand the symptoms associated with performing exercise and the impact of exercise intolerance on social, functional and emotional functioning on individuals with CHF.

One optional semi-structured interviews will be conducted with the participants who provide consent to participate in this part of the study (n = 28 or until saturation in findings) once they have completed the Parts I and II. Participants may choose to opt out from this part of the study and this option will be included in the consent form. An interview specific topic guide has been developed on symptoms associated with performing physical activity and on the impact of exercise intolerance on quality of life. Data from the semi-structured interviews will be analysed thematically using an inductive approach. All interviews will be transcribed verbatim. The interviews will be conducted remotely and participants will be given the option to use the zoom platform or receive a telephone call.

Sample size and statistical analysis:

The target sample size is based on a power calculation using the expected effect moderate effect size for a positive effect of nitrate supplementation on exercise tolerance derived from previous research. For an a of 0.05 and a power of 0.80, a total sample size of 24 is required. To account for potential drop-outs, an additional 4 participants will be recruited, based on drop-out rate of \~20% in studies assessing the effect of nitrate supplementation on exercise tolerance. For Part I, the analysis will include a two-way repeated measures analysis of variance (ANOVA) to determine the effect of the magnitude of active muscle mass (small vs. large) on neuromuscular fatigability and other physiological variables measured during cycling. For Part II, the analysis will include a two-way repeated measures ANOVA to determine the effect of nitrate supplementation vs. placebo on neuromuscular fatigability and other physiological variables measured during cycling. For Part III, an inductive approach to analysis will be made and data saturation of themes will be determined at the analysis stage. Two independent reviewers in the research study team will code and extract segments of the data to identify key themes. Inclusion of supporting quotes from each of the themes will be included in the write up and publication.

Funding:

The study is funded through a studentship offered by the Faculty of Medical Sciences, Newcastle University.

• Voluntary activation [Time frame: 3 years]
• Resting evoked twitch force [Time frame: 3 years]
• Electromyography [Time frame: 3 years]
• Time constant for recovery of muscle oxygen uptake [Time frame: 3 years]
• Microvascular responsiveness [Time frame: 3 years]
• Cardiac output [Time frame: 3 years]
• Stroke volume [Time frame: 3 years]
• Heart rate [Time frame: 3 years]
• Mean arterial blood pressure [Time frame: 3 years]
• Oxygen consumption [Time frame: 3 years]
• Carbon dioxide production [Time frame: 3 years]
• Ventilation [Time frame: 3 years]