Objective: Long COVID is complicated by endothelial and microvascular dysfunction, contributing to increased cardiovascular risk. Nicotinamide adenine dinucleotide (NAD+) regulates redox balance, inflammatory signaling, and endothelial homeostasis, and its disruption during SARS-CoV-2 infection may have lasting vascular consequences. This study aimed to characterize alterations in NAD+ metabolism in Long COVID and their associations with inflammation, endothelial activation, and microcirculatory function. Design and method: Patients with Long COVID and cardiovascular symptoms were enrolled alongside healthy controls. Microcirculatory function was assessed noninvasively using Flow-Mediated Skin Fluorescence (FMSF), skin reduced NAD+ (NADH) fluorescence during ischemic and hyperemic conditions. Erythrocyte concentrations of NAD+, NADH, and NADP were measured by high-performance liquid chromatography to assess intracellular redox status. Plasma levels of NAD+ precursors and degradation products were quantified using targeted mass spectrometry–based metabolomics. Systemic inflammation and endothelial activation were evaluated by high-sensitivity C-reactive protein (hsCRP), tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10), and soluble intercellular adhesion molecule-1 (sICAM-1) with ELISA or on a Luminex platform. Results: Long COVID patients exhibited impaired FMSF-derived microcirculatory parameters accompanied by a significantly reduced cellular NAD+/NADH ratio (47.15 ± 8.51 vs. 108.8 ± 29.22) and decreased NADP levels compared with controls, indicating persistent redox imbalance. Plasma metabolomic profiling revealed reduced availability of NAD+ precursors and accumulation of terminal degradation products, including 4PYR (0.036 ± 0.004 vs. 0.016 ± 0.007 μmol/L) and Met2PY (0.77 ± 0.07 vs. 0.38 ± 0.08 μmol/L). Met2PY concentrations correlated positively with hsCRP, an unfavorable TNF-alpha/IL-10 ratio, increased sICAM-1 levels, and impaired FMSF indices. In contrast, concentrations of the NAD+ precursor nicotinamide riboside (NR) were associated with improved endothelial reactivity, lower levels of endogenous endothelial nitric oxide synthase inhibitors, and better microvascular function. Conclusions: Persistent disturbances in NAD+ metabolism link chronic inflammation with endothelial and microvascular dysfunction in Long COVID. Accumulation of toxic NAD+ degradation products, particularly Met2PY, identifies patients at increased vascular risk, whereas NR availability appears protective. FMSF enables sensitive, noninvasive detection of these alterations. Therapeutic strategies aimed at restoring NAD+ homeostasis and limiting harmful metabolite accumulation may mitigate long-term cardiovascular complications in Long COVID.
Mierzejewska et al. (Fri,) studied this question.