Exploring trimethylamine n-oxide's role in coronary microvascular dysfunction and prognostic outcomes in ST-elevation myocardial infarction patients

Abstract Background Coronary microvascular dysfunction (CMD) subsequent to ST-elevation myocardial infarction (STEMI) is increasingly recognized as a determinant of adverse clinical prognoses. Despite its significance, CMD diagnosis is rare in clinical settings, mainly due to its complexity and technical challenges. Considering these challenges, this study endeavors to explore the diagnostic potential of Trimethylamine N-oxide (TMAO), a metabolite derived from gut microbiota. TMAO has been implicated in the pathogenesis of endothelial dysfunction and atherosclerosis, suggesting its utility as a novel biomarker for CMD and determining prognosis. Purpose To investigate the association between TMAO levels and CMD in STEMI patients, evaluating TMAO's utility as a biomarker for CMD and prognosis predictor. Methods In this prospective, observational study, 210 STEMI patients were enrolled. At the 3-month follow-up, these patients were subjected to comprehensive coronary physiology assessments, including measurements of coronary flow reserve (CFR), fractional flow reserve (FFR), and the index of microcirculatory resistance (IMR) via utilization of pressure-temperature sensor-tipped wires. CMD was diagnosed in patients presenting with an IMR ≥ 25 or a CFR < 2.0, alongside an FFR > 0.80. Levels of TMAO, C-reactive protein (CRP), and brain natriuretic peptide (BNP), along with other traditional biomarkers were measured at baseline, 3 and 12-month follow-up. Using the Delong test and Youden index to find optimal TMAO cutoffs for CMD detection, due to no predefined TMAO threshold. The primary endpoint was the incidence of CMD at 3 months, with the secondary endpoint being major adverse cardiovascular and cerebrovascular events (MACCE) at 12 months. Results Among enrolled patients, 85 (40.5%) were female, with a median age of 65 (IQR: 58-76). TMAO's baseline receiver operating characteristic (ROC) curve area was 0.55 (95% CI: 0.46-0.64; p=0.426), improving to 0.80 (95% CI: 0.73-0.87; P<0.001) at 3-month follow-up. An optimal TMAO cutoff of 3.91 μM achieved 75% sensitivity (95% CI: 0.63-0.86) and 82% specificity (95% CI: 0.76-0.88), outperforming BNP and CRP with ROC areas of 0.62 and 0.67, respectively. Patients were divided into low (n=140) and high (n=70) TMAO groups at the 3.91 μM threshold. A higher percentage of females was noted in the high TMAO group (55.7% vs. 32.9%; p<0.001). Clinical characteristics and risk factors like stroke and CAD history showed no significant differences across TMAO groups. Multivariable logistic regression revealed TMAO levels at 3 months as an independent predictor for CMD. A cubic spline curve indicated a marked increase in CMD odds with TMAO between 3 and 6 μM.The Incidence of MACCE was significantly higher in patients with a TMAO≥3.91 (41.4% vs 10.7%; p < 0.001). Conclusion Elevated TMAO levels 3 months post-STEMI are significantly associated with increased CMD risk, and significantly predict MACCE.TMAO as a Biomarker for CMD and MACCETMAO Cubic Spline Analysis for CMD Odds