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Review
. 2022 Jul 15:9:940832.
doi: 10.3389/fcvm.2022.940832. eCollection 2022.

Overstimulation of the ergoreflex-A possible mechanism to explain symptoms in long COVID

Shirley Sze  1 , Daniel Pan  2   3 , Alastair J Moss  1 , Cheng Ken Ong  4 , Manish Pareek  2   3 , Iain B Squire  1 , Andrew L Clark  5
Affiliations
Review

Overstimulation of the ergoreflex-A possible mechanism to explain symptoms in long COVID

Shirley Sze et al. Front Cardiovasc Med. .

Abstract

Long COVID refers to a multitude of symptoms that persist long after SARS-CoV-2 infection. Fatigue and breathlessness are the most common symptoms of long COVID across a range of studies. They are also cardinal symptoms of chronic heart failure (CHF). In this review, we propose that fatigue and breathlessness in patients with long COVID may be explained by skeletal muscle abnormalities, in a manner similar to patients with CHF. The ergoreflex is a cardiorespiratory reflex activated by exercise, which couples ventilation and cardiovascular function to exercise intensity. At least part of the symptomatology of CHF is related to abnormal skeletal muscle and an enhanced ergoreflex, resulting in heightened sympathetic, vasoconstrictor and ventilator drives. Similarly, SARS-CoV-2 infection results in a hyperinflammatory and hypercatabolic state. This leads to reduction in skeletal muscle mass and altered function. We postulate that the ergoreflex is chronically overstimulated, resulting in fatigue and breathlessness. Exercise training preserves muscle mass and function as well as reduces ergoreflex activation; therefore may have a role in improving symptoms associated with long COVID. Should the ergoreflex be proven to be an important pathophysiological mechanism of long COVID, tailored exercise interventions should be trialed with the aim of improving both symptoms and perhaps outcomes in patients with long COVID.

Keywords: breathlessness; ergoreflex; fatigue; heart failure; long COVID; pathophyisology.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
An illustration of the ergoreflex. Skeletal muscle exercise causes stimulation of the metabo- and mechano-receptors. The signals are integrated centrally and contribute to the ventilatory and cardiovascular responses to exercise. Exaggerated ergoreflex (e.g., heart failure) leads to excessive response relative to work performed, leading to the sensation of breathlessness and fatigue.
FIGURE 2
FIGURE 2
The ergoreflex in chronic heart failure. Following handgrip dynamometer exercise to exhaustion, a cuff is either inflated around the exercising arm at peak exercise (solid line) or not (dotted line). The cuff is deflated after 3 min (end of circulatory occlusion in gray box). Compared to controls, patients with heart failure have an exaggerated ergoreflex response, resulting in greater ventilatory response to exercise. Their ventilatory response is maintained at the same level as maximum exertion throughout circulatory occlusion. Adapted from Piepoli et al. (11).
FIGURE 3
FIGURE 3
We propose ergoreflex overstimulation as a possible pathophysiological mechanism of long COVID. Acute COVID-19 infection predisposes to insulin resistance and sympathetic and renin-angiotensin-aldosterone system overstimulation, which may lead to chronic inflammation and hypercatabolism. This in turn can cause reduction in skeletal mass and function, which increases ergoreflex sensitivity, and perhaps explains the symptoms of long COVID such as breathlessness and fatigue. Solid and dotted arrows represent known and hypothetical relations, respectively.
See this image and copyright information in PMC

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