Abstract 4143985: Post-acute Sequelae of COVID-19 (PASC) is Related to Endothelial Dysfunction and Elevated Asymmetric-dimethylarginine

Introduction: Endothelial dysfunction can trigger the development and progression of cardiovascular disease. We hypothesize that cardiovascular PASC is induced by persistent endothelial dysfunction mediated via asymmetric-dimethylarginine (ADMA, the endogenous inhibitor of endothelial nitric oxide synthase). ADMA levels rise in response to viral infections, but it is usually degraded by the enzyme DDAH1, which is inhibited by chronic inflammation and oxidative stress. This study aims to determine whether cardiovascular PASC is associated with endothelial dysfunction and to clarify the role of ADMA in this relationship. Methods: We recruited subjects who had been previously infected and developed cardiovascular symptoms (PASC+), those who had been infected but did not have PASC (PASC-), and those who had never been infected (controls) (n=20 each). Groups were matched for age, sex, and BMI and underwent blood draws and fat biopsies. Vascular function was assessed in-vivo via ultrasound imaging and ex-vivo in fat-isolated arterioles. Results: Compared to PASC- and controls, PASC+ subjects exhibited 80% higher serum levels of ADMA and 40% reduced nitric oxide levels. DDAH1 activity was elevated in the PASC+, suggesting a compensatory mechanism for the elevated ADMA levels. However, PASC+ obese subjects exhibited substantially lower DDAH1 activity than non-obese subjects, which was associated with lower insulin sensitivity and higher ADMA levels. Compared to the other two groups, the PASC+ group exhibited lower brachial artery vasoreactivity, while nitroglycerin-induced dilation did not differ statistically, suggesting impaired endothelial function. In the PASC+ group, microvascular recruitment in response to reactive hyperemia was diminished, as was the ex vivo measured flow-induced arteriolar dilation and NO generation. Left ventricle (LV) dysfunction was observed in 80% of the PASC+ group, as opposed to 5% of the PASC- and controls. The LV ejection fraction and global longitudinal strain (GLS) were substantially reduced in the PASC+ group, which was correlated with higher ADMA, C-reactive protein, and troponin-1, as well as lower NO and vascular function. Obese PASC+ subjects had the highest ADMA and the lowest endothelial-dependent vasodilation and insulin sensitivity. Conclusion: Cardiovascular PASC symptoms are related to persistent endothelial dysfunction and elevated ADMA levels, which may be further exacerbated by obesity and reduced DDAH1 activity.