TMAO: a potential mediator of clopidogrel resistance

Ruisong Ma,Jing Zhang,Jun Yang,Hong Jiang,Hong Jiang,Wenwen Fu,Wenwen Fu,Xiaorong Hu,Xiaorong Hu

doi:10.1038/s41598-021-85950-8

Abstract

Trimethylamine-N-oxide (TMAO) can activate platelets and increase thrombosis risk in clinical and experimental models. Meanwhile, the patients with coronary artery disease have higher serum TMAO level. However, it remains unknown whether Clopidogrel Resistance (CR) could be attributed to TMAO. The present study aimed investigate the effects of TMAO on clopidogrel in ischemia and reperfusion (IR) model in rats. Clopidogrel could (1) promote the production of platelets, induce an increase in the platelet-larger cell ratio; (2) prolong the tail bleeding time; (3) reduce platelet aggregation function, induced by ADP, and alleviate myocardial thrombus burden. TMAO could partially offset the effects of clopidogrel and induce CR. Thus, the present study demonstrated that circulating TMAO could reduce the inhibitory effects of clopidogrel on platelet aggregation. TMAO may be a potential mediator of clopidogrel resistance.

Highlights

Trimethylamine-N-oxide (TMAO) can activate platelets and increase thrombosis risk in clinical and experimental models
Compared with the values for the clopidogrel + ischemia and reperfusion (IR) group, the addition of TMAO had no significant effect on the PLT count (861.17 ± 216.12 × 10^9 pcs/L, P > 0.05), platelet-larger cell ratio (P-LCR) (7.28 ± 2.45%, P > 0.05) or mean platelet volume (MPV) (7.28 ± 0.39 fL, P > 0.05) (Fig. 1)
No Clopidogrel Resistance (CR) was observed in the clopidogrel + IR group (0/7), and two cases with CR were observed in the TMAO + clopidogrel + IR group (2/6)

Summary

Introduction

Trimethylamine-N-oxide (TMAO) can activate platelets and increase thrombosis risk in clinical and experimental models. The patients with coronary artery disease have higher serum TMAO level. It remains unknown whether Clopidogrel Resistance (CR) could be attributed to TMAO. The present study aimed investigate the effects of TMAO on clopidogrel in ischemia and reperfusion (IR) model in rats. The present study demonstrated that circulating TMAO could reduce the inhibitory effects of clopidogrel on platelet aggregation. Elevated serum TMAO levels are independently associated with coronary artery disease development and have predicted an increased thrombotic event risk in large-scale clinical studies[13,15,16]. Whether the hyperresponsiveness of platelets induced by TMAO could affect the antiplatelet activity of clopidogrel and whether the elevated TMAO level in CAD patients is a potential contributor to clopidogrel resistance remain unclear. We will explore the above questions in an ischemia and reperfusion (IR) model in rats

Methods

Results

Conclusion