What question did this study set out to answer?

This study aims to investigate the changes in NAD+ metabolism in Long COVID and how these relate to inflammation and vascular health.

June 3, 2026

Persistent Metabolic Dysregulation Links Inflammation With Endothelial and Microvascular Dysfunction in Long Covid

Key Points

This study aims to investigate the changes in NAD+ metabolism in Long COVID and how these relate to inflammation and vascular health.
Patients with Long COVID and cardiovascular symptoms were compared to healthy controls.
Microcirculatory function was assessed using Flow-Mediated Skin Fluorescence (FMSF) and biomarker analysis through ELISA and Luminex.
NAD+ and its derivatives were measured using high-performance liquid chromatography and mass spectrometry.
Long COVID patients showed a lower NAD+/NADH ratio (47.15 vs. 108.8, p<0.001), indicating redox imbalance.
Significant reductions in NAD+ precursors and increased levels of degradation products like 4PYR were noted (0.036 vs. 0.016 μmol/L, p<0.01).
Higher Met2PY levels correlated with increased hsCRP and impaired FMSF indices, suggesting inflammation links to vascular malfunction.

Abstract

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.

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