Trimethylamine N-Oxide and Stroke Recurrence Depends on Ischemic Stroke Subtypes

Abstract

Background and Purpose: Trimethylamine N-oxide (TMAO) has been recognized as a risk factor for cardiovascular disease. However, the role of TMAO in ischemic stroke remains unclear. As we know, ischemic stroke is a heterogeneous disease with variable pathogenesis. Hence, we aimed to investigate the association between TMAO and stroke recurrence according to etiology subtypes. Methods: A total of 10 756 ischemic stroke/transient ischemic attack patients from the Third China National Stroke Registry were enrolled, and 1-year follow-up data for stroke recurrence were analyzed. TOAST (Trial of ORG 10172 in Acute Stroke Treatment) criteria was used to classify the etiology subtypes. Plasma TMAO levels were quantified by liquid chromatography–mass spectrometry. The association between TMAO and stroke outcomes was analyzed using Cox regression models. We also conducted a meta-analysis on the association of TMAO levels and stroke risk. Results: Elevated TMAO level was independently associated with the risk of stroke recurrence (Q4 versus Q1: adjusted hazard ratio, 1.37 [95% CI, 1.15–1.64]) in multivariate Cox regression model. After stratification by TOAST subtypes, there was a significant association between TMAO and stroke recurrence in small artery occlusion subtype (adjusted hazard ratio, 1.43 [95% CI, 1.03–2.00]) but not in the others subtype (large-artery atherosclerosis, 1.19 [0.95–1.48]; cardioembolism, 1.54 [0.95–2.48]; others, 1.19 [0.98–1.44]). The meta-analysis reported on stroke recurrence for the highest versus lowest TMAO levels with a pooled hazard ratio of 1.66 (95% CI, 0.91–3.01) and similarly found an increased risk of stroke recurrence. Conclusions: Elevated TMAO level is associated with increased risk of stroke recurrence in patients with small artery occlusion subtype, but this association seems to be attenuated in large-artery atherosclerosis, cardioembolism, and others subtypes.

Effects of acute administration of trimethylamine N-oxide on endothelial function: a translational study

“…We did not observe sex-dependent differences in the TMAO concentration in healthy and obese patients before and after RYGB or diet-treatment (SOM 1 A,B), similar to previous reports performed in healthy as well as in overweight/obese, pre-diabetic or CVD, stroke patients 1 , 34 , 36 , 37 . On the contrary, some studies measured higher TMAO levels in healthy men 35 , while in mice, higher circulating TMAO levels were observed in female animals 1 , 2 .…”

“…We confirmed a high variability in circulating fasting TMAO levels showing a large overlap between patients and healthy controls. Since a clear definition of physiological TMAO levels is missing, there are large differences across individual studies, which make difficult to identify thresholds to distinguish TMAO levels in health and disease states 10 , 37 . In this study, TMAO was tested in serum, in which concentrations of TMAO are more stable compared to citrate plasma 38 .…”

“…Ischemic stroke is a heterogeneous disease with variable pathogenesis. It is currently debated whether TMAO is really an atherogenic factor or whether variations in its concentrations just reflect the presence of cardiovascular and metabolic risk factors associated with ischemic stroke 37 . Patients with recurrent stroke displayed higher plasma TMAO levels than those without recurrent stroke at 1-year follow-up (recurrent stroke TMAO average: 6.86 μM) 22 .…”

Nontraditional Risk Factors for Residual Recurrence Risk in Patients with Ischemic Stroke of Different Etiologies

“…In order to evaluate nontraditional risk factors for stroke comprehensively, we have multidimensionally selected some factors that may be associated with stroke and indicators that are still controversial for analysis, in- cluding inflammation levels reflected by hs-CRP and IL-6 [13,14], renal dysfunction reflected by eGFR [15,16], cystatin C [17] which was also related to renal dysfunction, hyperhomocysteinemia [18], TMAO [19], coagulation, and thrombosis status reflected by fibrinogen, and uric acid levels. In this study, LAA and SAO subtypes owned their specific nontraditional risk factors, while inflammation was the common risk factor for residual recurrence risk of both.…”

Elevated lipoprotein(a) and lipoprotein-associated phospholipase A2 are associated with unfavorable functional outcomes in patients with ischemic stroke

“…An electronic data capture system by face-to-face interviews was used to collect CNSR-III clinical baseline data. The subsequent data were gathered from the registry database, including age, sex, body mass index (BMI), and smoking status; medical history of hypertension, diabetes mellitus, hyperlipidemia and transient ischemic attack (TIA); systolic blood pressure (SBP), fasting plasma glucose (FPG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), high-sensitivity C-reactive protein (hsCRP), and lipoprotein-associated phospholipase A 2 [Lp-PLA 2 ]; stroke subtypes, classified as large artery atherosclerosis (LAA), cardioembolism (CE), small artery occlusion (SAO), other determined cause, or undetermined cause according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) criteria [ 16 ], and other determined cause and undetermined cause are defined as Others [ 17 ], discharge medication rate of Lipid-lowering drugs and antiplatelet drugs, and the National Institutes of Health Stroke Scale (NIHSS) score at admission.…”