Peripheral Determinants of Oxygen Utilization During Exercise in HFpEF

Rates of hospitalization for acute decompensated heart failure have increased in the United States in recent years, according to a study published in 2018.¹ Between 2005 and 2014, the average annual increase was 4.3% among Black women, 3.7% among Black men, 1.9% among White women, and 2.6% among White men. The authors cite a growing incidence of heart failure with preserved ejection fraction (HFpEF) as primary factor influencing these trends.

In addition to reduced functional capacity and quality of life, patients with HFpEF have substantial exercise intolerance, which may be due to peripheral factors such as reduced arteriovenous oxygen content difference (ΔAVO₂) at peak exercise. Although it has been proposed that reduced ΔAVO₂ may reflect impairments within the skeletal muscle, the authors of a study published in March 2020 note that ΔAVO₂ is a complex metric incorporating “skeletal muscle blood flow and skeletal muscle diffusional conductance for oxygen (DmO₂) across the skeletal muscle capillary membrane” and is “not dependent solely on skeletal muscle properties.”²

Assessment of DmO₂ thus provides a more accurate measure of “skeletal muscle properties than ΔAVO₂, incorporating features such as capillarity, fiber size, and fiber composition into its determination,” they noted.² To explore whether reduced DmO₂ may explain reductions in ΔAVO₂ in HFpEF, the researchers assessed ΔAVO₂ and DmO₂ during exercise in 20 adults with HFpEF and in 20 healthy control individuals, as well as in an additional control group of 19 individuals with hypertension but no symptoms of heart failure.

Although ΔAVO₂ was reduced in the HFpEF group during both systemic (cycle ergometry) and local (forearm handgrip) exercise, there was no difference in forearm DmO₂ between groups during maximal-effort handgrip exercise, contrary to the expectation of lower DmO₂ in the HFpEF group. This finding obviates compromised oxygen diffusion as a potential mechanism driving reduced forearm ΔAVO₂ in HFpEF.

However, performance on the forearm exercise predicted more than one-third of the variability in systemic aerobic capacity, suggesting a substantial influence of peripheral factors on whole-body exercise capacity. In addition, a strong correlation was found between the degree of adiposity measured with whole-body X-ray absorptiometry and ΔAVO₂, indicating the possibility of ”an active role for adipose tissue in reducing exercise capacity in patients with HFpEF.”² As this observation aligns with results of recent clinical trials, the role of adipocytes in skeletal muscle function warrants attention in future studies, the authors concluded.³

For further discussion regarding these results, we checked in with lead author Payman Zamani, MD, MTR, associate professor of medicine in the division of cardiology at the Perelman School of Medicine at the University of Pennsylvania.

What do your findings add to our understanding of factors affecting exercise capacity in adults with HFpEF?

Dr Zamani: There is an abundance of evidence indicating abnormalities within the heart during exercise in HFpEF. Our work adds to the growing body of literature that also demonstrates abnormalities within “peripheral” structures that associate with diminished exercise capacity. For example, we found abnormalities in muscle oxygen extraction and utilization during cycle exercise, suggesting that the skeletal muscle may be playing a limiting role.

To look at this further, we studied forearm exercise, a type of exercise that does not tax the limits of cardiac output. During forearm exercise, we found abnormalities in muscle oxygen extraction and utilization.

We then found that the forearm diffusional conductance for oxygen, a metric describing the impediments to the movement of oxygen out of the capillaries and into the skeletal muscle mitochondria, was not abnormal in HFpEF and therefore could not explain the abnormal forearm skeletal muscle oxygen utilization. On the other hand, the degree of adiposity correlated with the reductions in oxygen utilization. 

What is the proposed mechanism by which adiposity might play a role in reducing exercise capacity in these patients?

Dr Zamani: How and if adiposity affects skeletal muscle oxygen utilization is not clear. It is possible that adipose tissue directly “steals” blood and nutrients away from the muscle during exercise. Alternatively, the increased adiposity could lead to inflammation or other factors which then impair skeletal muscle mitochondrial function, leading to a reduction in oxidative capacity.

What are the key clinical implications of your findings?

Dr Zamani: Our findings reinforce the importance of weight loss and exercise training in patients with HFpEF, both of which have been shown to improve exercise capacity.⁴ Exercise training has also been shown to specifically improve skeletal muscle oxygen utilization in HFpEF.⁵

What are some of the most notable remaining research needs in this area?

Dr Zamani: While observational and epidemiologic studies have shown associations between obesity and HFpEF, exactly how adiposity contributes to HFpEF development remains unclear. Moreover, the role of the skeletal muscle mitochondria in exercise intolerance in HFpEF is also unclear. This has potential therapeutic implications, as drugs that target the mitochondria are available.⁶

Disclosures: Dr Zamani has consulted for Vyaire

1. Chang PP, Wruck LM, Shahar E, et al. Trends in hospitalizations and survival of acute decompensated heart failure in four US communities (2005-2014): ARIC study community surveillance. Circulation. 2018;138(1):12-24. doi:10.1161/CIRCULATIONAHA.117.027551
2. Zamani P, Proto EA, Mazurek JA, et al. Peripheral determinants of oxygen utilization in heart failure with preserved ejection fraction: central role of adiposity. JACC Basic Transl Sci. 2020;5(3):211-225. doi:10.1016/j.jacbts.2020.01.003
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