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Back to the future: re-evaluation of the possible role for oxygen supplementation during exercise in chronic heart failure
  1. David L Prior
  1. Correspondence to Associate Professor David Prior, Department of Cardiology, University of Melbourne, St Vincent's Hospital Melbourne, PO Box 2900, Fitzroy, VIC 3065, Australia; david.prior{at}svha.org.au

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Reduced exercise capacity in heart failure

Reduced exercise tolerance is the key symptom in chronic heart failure (CHF) leading to reductions in functional status and quality of life. The underlying mechanisms behind the muscle fatigue and dyspnoea which limit exercise capacity in heart failure are very complex, with multiple factors in the chain from the heart and lungs to the muscles contributing to the symptoms. In addition to altered cardiac function and haemodynamics as the central initiator of the heart failure syndrome, abnormalities have been identified in pulmonary function, ventilatory efficiency, peripheral vascular and in particular endothelial function, skeletal muscle structure and skeletal muscle metabolism.

Over the last 20 years, the key role of the peripheral changes in skeletal muscle has been appreciated.1 Some of the changes which have been documented in the periphery and which may be important in causing reduced exercise tolerance include muscle wasting (especially in those with more advanced disease), a shift in muscle fibre type from type I fibres, which are relatively fatigue resistant, to type II fibres, and particularly type IIb fibres, which are less fatigue resistant and have reduced oxidative capacity. Ultrastructural myocyte changes have also been documented with reductions in the mitochondrial density and in oxidative enzymes. Reductions in oxygen delivery to working muscles have been identified in CHF with reduced capillary density seen in males with CHF.

One of the key physiological parameters which is strongly linked to exercise capacity in almost all settings is peak oxygen consumption (peak VO2).2 This exercise-derived parameter quantifies the body's ability to take up oxygen, deliver it to working muscle and use that oxygen to generate power. This is why athletes have developed training methods to improve peak oxygen consumption in order to improve endurance exercise capacity. Similarly, peak oxygen consumption remains an important marker of exercise capacity and prognosis in heart failure, with low peak VO2 used as a decision making tool for listing for heart transplantation and changes in peak VO2 used as an endpoint in clinical trials. The mechanism by which cardiac function is related to peak VO2 is in some ways simple with cardiac size, and peak cardiac output strongly related to this parameter. It is often pointed out that exercise capacity is poorly related to cardiac output in heart failure, although it should come as no surprise that resting cardiac output is unrelated to exercise capacity as most heart failure patients have normal resting cardiac output. This has lead to a focus on the key role of the periphery, although abnormalities of oxygen delivery to muscle have been identified at multiple levels.3 At the heart of this conundrum, however, delivery of oxygen to the exercise muscles remains a key problem.

Oxygen supplementation and exercise capacity in CHF

This has led researchers to ask whether simply increasing the concentration of inspired oxygen will improve oxygen delivery to the tissues and thereby improve exercise tolerance, a key component in the chronic disability caused by heart failure, resulting in reduced quality of life. Most studies exploring this question have been small, probably to the extent of being underpowered and have produced contradictory results. A study of 12 patients with CHF by Moore et al4 testing FiO2 of 21%, 30% and 50% showed increased exercise capacity, increased arterial oxygen saturation, reduced minute ventilation and subjective improvement in breathlessness with higher FiO2. Of note, the majority of these patients had CHF due to dilated cardiomyopathy. In contrast, a study by Restrick et al5 of 12 patients in whom the predominant cause of heart failure was coronary artery disease with previous myocardial infarction found that arterial oxygen saturation was increased by administration of 2 or 4 L/min of oxygen, but there was no improvement in exercise capacity or subjective breathlessness. A subsequent study by Russell et al6 using cycle ergometry in 16 patients with moderate heart failure symptoms and very low LVEF examining FiO2 of 21% and 60% again showed increased arterial oxygen concentrations at rest and during exercise, but showed no difference in exercise capacity with supplemental oxygen. Thus, the findings from small studies with differing populations using differing methodologies have been mixed and the subject has not been revisited more recently. The dogma has, however, been that supplemental oxygen is not beneficial in patients with CHF who are not hypoxic.

In a re-evaluation of this concept published in Heart by Koshy7 the authors have again examined whether increasing inspired oxygen concentration acutely improves exercise tolerance in patients with CHF and reduced left ventricular ejection fraction (LVEF). This study has a number of strengths, which warrant some consideration. The first is that the study is significantly larger than both previous key studies in this area with 31 participants thus increasing study power. The methodology was rigorous with a single blind cross-over design, with testing with and without supplemental oxygen conducted in randomised order to reduce the impact of a training effect. The use of three levels of inspired oxygen allowed them to look for a dose response, which could help to strengthen the credibility of the findings The patients had findings typical of New York Heart Association (NYHA) class II and III CHF with reduced ejection fraction with a mean LVEF of 31.4%, a median B-type natriuretic peptide (BNP) level of 1531 ng/L and were on guideline recommended therapies in the majority of cases. The participants were not hypoxic at rest. The investigators found that increased FIO2 improved exercise capacity when measured by multiple parameters, resulted in improved arterial O2 saturations during exercise and that heart rate was lower at any given workload with higher FIO2. They observed that most gains were seen at the FiO2 of 0.28 although arterial oxygen saturations were highest with an FiO2 of 0.4. Their findings raise the possibility that a relatively simple intervention may help improve functional capacity and thus quality of life in a group of patients in whom small gains can carry great functional significance.

Areas of uncertainty

Aside from the fact that the population was predominantly male despite the authors inviting similar numbers of males and females to participate in the study, one weakness of the study is its simple design which makes the findings easy to interpret, but gives little insight into the possible mechanisms for the findings. We are thus left with improvements in the important endpoint of exercise capacity, but little understanding of the dominant mechanism. Is it due to changes in pulmonary vasculature and nervous system responses to exercise or muscle uptake of oxygen? It is also unclear for which heart failure patients this finding may be relevant. Does it apply to more advanced heart failure or have the peripheral changes important in exercise become too severe to be impacted by supplemental oxygen? Could this be relevant in heart failure with preserved ejection fraction, a condition with almost no therapies proven to be beneficial? In addition, we do not know if a benefit seen on a single episode of exercise with increased FiO2 will be seen on subsequent occasions or whether chronic use may have other adverse outcomes.

The work of Koshy suggests that we should not dismiss the possible benefits of oxygen on exercise capacity. The findings need to be reproduced in a study of similar or larger size, we need to understand the mechanism of benefit through more detailed physiological studies of each part in the chain of oxygen delivery and the effects of chronic oxygen supplementation during exercise need to be explored. What appears important is that we should revisit old ideas from time to time, and if the evidence is not conclusive or the tools available to study a problem have changed, they may be worth re-evaluation.

References

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Footnotes

  • Competing interests None declared.

  • Provenance and peer review Commissioned; internally peer reviewed.

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