Red Blood Cell Adenylate Energetics Is Related to Endothelial and Microvascular Function in Long COVID

Abstract

Adenine nucleotides play a critical role in maintaining essential functions of red blood cells (RBCs), including energy metabolism, redox status, shape fluctuations and RBC-dependent endothelial and microvascular functions. Recently, it has been shown that infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) might lead to morphological and metabolic alterations in erythrocytes in both mild and severe cases of coronavirus disease (COVID-19). However, little is known about the effects of COVID-19 on the nucleotide energetics of RBCs nor about the potential contribution of nucleotide metabolism to the long COVID syndrome. This study aimed to analyze the levels of adenine nucleotides in RBCs isolated from patients 12 weeks after mild SARS-CoV-2 infection who suffered from long COVID symptoms and to relate them with the endothelial and microvascular function parameters as well as the rate of peripheral tissue oxygen supply. Although the absolute quantities of adenine nucleotides in RBCs were rather slightly changed in long COVID individuals, many parameters related to the endothelial and microcirculatory function showed significant correlations with RBC adenosine triphosphate (ATP) and total adenine nucleotide (TAN) concentration. A particularly strong relationship was observed between ATP in RBCs and the serum ratio of arginine to asymmetric dimethylarginine—an indicator of endothelial function. Consistently, a positive correlation was also observed between the ATP/ADP ratio and diminished reactive hyperemic response in long COVID patients, assessed by the flow-mediated skin fluorescence (FMSF) technique, which reflected decreased vascular nitric oxide bioavailability. In addition, we have shown that patients after COVID-19 have significantly impaired ischemic response parameters (IR max and IR index), examined by FMSF, which revealed diminished residual bioavailability of oxygen in epidermal keratinocytes after brachial artery occlusion. These ischemic response parameters revealed a strong positive correlation with the RBC ATP/ADP ratio, confirming a key role of RBC bioenergetics in peripheral tissue oxygen supply. Taken together, the outcomes of this study indicate that dysregulation of metabolic processes in erythrocytes with the co-occurring endothelial and microvascular dysfunction is associated with diminished intracellular oxygen delivery, which may partly explain long COVID-specific symptoms such as physical impairment and fatigue.

Special Issue “Latest Research in Post-COVID (Long COVID): Pathological and Treatment Studies of Sequelae and Complications”

“…In accordance with the hypothesized endothelial problems, another study published in this Special Issue found that pulmonary embolism, as well as the use of a high-flow nasal cannula and prolonged hospitalization, is associated with reduced functional capacity and a higher likelihood of exertional desaturation in patients with post-COVID-19 condition [37]. Thus, the association of endothelial and microvascular dysfunction with reduced intracellular oxygen delivery may partly explain this post-COVID fatigue and limited functional capacity [36]. Similarly, the endothelial disfunction of the brain would explain the presence of post-COVID cognitive symptomatology [38].…”

“…In this last section, the remaining papers are summarized. Romanowska-Kocejko et al observed that the dysregulation of metabolic processes in erythrocytes, in addition to endothelial and microvascular dysfunction, is associated with the decreased delivery of intracellular oxygen in patients with post-COVID-19 condition [36]. In accordance with the hypothesized endothelial problems, another study published in this Special Issue found that pulmonary embolism, as well as the use of a high-flow nasal cannula and prolonged hospitalization, is associated with reduced functional capacity and a higher likelihood of exertional desaturation in patients with post-COVID-19 condition [37].…”

A New Approach to the Assessment of Erectile Dysfunction Based on Vasomotion Monitored by the Flow-Mediated Skin Fluorescence (FMSF) Technique—A Preliminary Study

“…A new diagnostic technique named Flow-Mediated Skin Fluorescence (FMSF), which enables a noninvasive evaluation of the vascular circulation and metabolic regulation, was introduced in 2017 [17][18][19][20][21]. The FMSF technique is based on monitoring the intensity of nicotinamide adenine dinucleotide (NADH) fluorescence from skin tissue on the forearm in response to blocking and releasing blood flow as a function of time.…”