The Influence of Active Muscle Mass and Nitrate Supplementation on 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: