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Research Article: Endothelial and cardiac dysfunction in long COVID With cardiovascular symptoms is associated with imbalance in the ADMA–DDAH–NOx pathway

Date Published: 2026-04-21

Abstract:
Post-acute sequelae of COVID-19 (PASC) commonly feature lingering symptoms of persistent cardiovascular pathology, yet the mechanisms remain incompletely defined. The ADMA–DDAH–NO x axis is a central regulator of endothelial function: ADMA inhibits endothelial NOx synthase, while DDAH clears most circulating ADMA. Although ADMA is linked to acute COVID-19 severity, its regulation in PASC remains largely unknown. We performed integrated vascular and cardiac phenotyping in 49 RECOVER participants: never-infected controls ( n =?10), recovered COVID-19 without persistent symptoms (PASC?, n =?20), and PASC with persistent cardiovascular-related symptoms lasting ?12 weeks post-infection (PASC+, n =?19). We measured ADMA, DDAH, NO, inflammatory/coagulation markers, endothelial function [brachial and microvascular flow-mediated dilation (FMD)], and cardiac structure and function using comprehensive echocardiography with speckle-tracking strain. PASC+ exhibited the highest inflammatory and thrombotic markers, with D-dimer being?>?3-fold higher than controls, and hs-CRP nearly threefold higher. PASC+ demonstrated lower NOx and substantially higher ADMA than the other two groups, accompanied by only modest DDAH upregulation, suggesting insufficient counter-regulation. Endothelial function was significantly impaired in the PASC+ group compared to the control and PASC- groups, as evidenced by lower brachial and microvascular FMD. PASC+ individuals exhibited worse longitudinal mechanics and higher levels of hs-troponin and NT-proBNP. Ejection fraction was lower in PASC+ compared with Controls and PASC?. These findings identify an imbalance in the ADMA–DDAH–NO x axis that is associated with endothelial dysfunction and cardiac involvement in cardiovascular-symptom PASC, supporting a potentially targetable pathway for risk stratification and therapeutic investigation.

Introduction:
Post-acute sequelae of COVID-19 (PASC) commonly feature lingering symptoms of persistent cardiovascular pathology, yet the mechanisms remain incompletely defined. The ADMA–DDAH–NO x axis is a central regulator of endothelial function: ADMA inhibits endothelial NOx synthase, while DDAH clears most circulating ADMA. Although ADMA is linked to acute COVID-19 severity, its regulation in PASC remains largely unknown.

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