Association of Circulating Metabolites With Racial Disparities in Hypertension and Stroke in the REGARDS Study

Kijpaisalratana, Naruchorn; Ament, Zsuzsanna; Patki, Amit; Bhave, Varun; Guarniz, Ana-Lucia Garcia; Judd, Suzanne E.; Cushman, Mary; Long, D. Leann; Irvin, Marguerite R.; Kimberly, W. Taylor

doi:10.1212/wnl.0000000000207264

Cited by 9 publications

(11 citation statements)

References 38 publications

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“…In addition, the metabolite measurements were quality controlled and normalized across batches by including human pooled plasma samples at regular intervals of every 10 injections. All metabolite level values were rank-based inverse normal transformed before statistical analysis since they did not conform to a normal distribution …”

Section: Methodsmentioning

confidence: 99%

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Trimethylamine N-Oxide and White Matter Hyperintensity Volume Among Patients With Acute Ischemic Stroke

Kijpaisalratana,

Ament,

Bevers

et al. 2023

JAMA Netw Open

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ImportanceAlthough increasing evidence suggests that trimethylamine N-oxide (TMAO) is associated with atherosclerosis, little is known about whether TMAO and its related metabolites (ie, choline, betaine, and carnitine) are associated with small vessel disease.ObjectiveTo evaluate the association between TMAO and its related metabolites with features of cerebral small vessel disease, including white matter hyperintensity volume (WMHV) and acute lacunar infarction.Design, Setting, and ParticipantsThis cross-sectional study included patients enrolled in the Specialized Programs of Translational Research in Acute Stroke biorepository. The registry included 522 patients with acute ischemic stroke who were 18 years or older who presented at the Massachusetts General Hospital or Brigham and Women’s Hospital within 9 hours after onset between January 2007 and April 2010. The analyses in this study were conducted between November 2022 and April 2023.ExposuresPlasma TMAO, choline, betaine, and carnitine were measured by liquid chromatography–tandem mass spectrometry.Main Outcomes and MeasuresWMHV was quantified by a semiautomated approach using signal intensity threshold with subsequent manual editing. Ischemic stroke subtype was classified using the Causative Classification System.ResultsAmong 351 patients included in this study, the mean (SD) age was 69 (15) years; 209 patients (59.5%) were male and had a median (IQR) admission National Institute of Health Stroke Scale of 6 (3-13). The magnetic resonance imaging subgroup consisted of 291 patients with a mean (SD) age of 67 (15) years. Among these, the median (IQR) WMHV was 3.2 (1.31-8.4) cm3. TMAO was associated with WMHV after adjustment for age and sex (β, 0.15; 95% CI, 0.01-0.29; P &lt; .001). TMAO remained significant in a multivariate analysis adjusted for age, sex, hypertension, diabetes, and smoking (β, 0.14; 95% CI, 0-0.29; P = .05). TMAO was associated with lacunar stroke but not other ischemic stroke subtypes in a model adjusted for age, sex, hypertension, diabetes, and smoking (OR, 1.67; 95% CI, 1.05-2.66; P = .03).Conclusions and RelevanceIn this observational study, TMAO was associated with cerebral small vessel disease determined by WMHV and acute lacunar infarction. The association was independent of traditional vascular risk factors.

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Section: Methodsmentioning

confidence: 99%

“…All metabolite level values were rank-based inverse normal transformed before statistical analysis since they did not conform to a normal distribution. 22 , 23 , 24 …”

Section: Methodsmentioning

confidence: 99%

Trimethylamine N-Oxide and White Matter Hyperintensity Volume Among Patients With Acute Ischemic Stroke

Kijpaisalratana,

Ament,

Bevers

et al. 2023

JAMA Netw Open

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“…Additionally, N -acetyl-tryptophan protects against hepatic ischemia-reperfusion injury through the RIP2/caspase-1/IL-1β signaling pathway; however, its effects on ischemic cardiomyopathy remain unclear. 44 Gluconic acid, a substance produced through the aerobic oxidation of glucose, 45 has been associated with oxidative stress, 46 hyperglycemia, and hypertension; 47 however, evidence directly linking it to CHD is unavailable. The potential relationship between these metabolites and CHD remains a vital and challenging research area.…”

Section: Discussionmentioning

confidence: 99%

Plasma Metabolic Profiling and Multiclass Diagnostic Model Development for Stable Angina Pectoris and Acute Myocardial Infarction

Lu,

Lin,

Jin

et al. 2024

ACS Omega

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Coronary heart disease remains a major global health challenge, with a clear need for enhanced early risk assessment. This study aimed to elucidate metabolic signatures across various stages of coronary heart disease and develop an effective multiclass diagnostic model. Using metabolomic approaches, gas chromatography−mass and liquid chromatography−tandem mass spectrometry were used to analyze plasma samples from healthy controls, patients with stable angina pectoris, and those with acute myocardial infarction. Pathway enrichment analysis was conducted on metabolites exhibiting significant differences. The key metabolites were identified using Random Forest and Recursive Feature Elimination strategies to construct a multiclass diagnostic model. The performance of the model was validated through 10-fold cross-validation and evaluated using confusion matrices, receiver operating characteristic curves, and calibration curves. Metabolomics was used to identify 1491 metabolites, with 216, 567, and 295 distinctly present among the healthy controls, patients with stable angina pectoris, and those with acute myocardial infarction, respectively. This implicated pathways such as the glucagon signaling pathway, D-amino acid metabolism, pyruvate metabolism, and amoebiasis across various stages of coronary heart disease. After selection, testosterone isobutyrate, N-acetyl-tryptophan, D-fructose, L-glutamic acid, erythritol, and gluconic acid were identified as core metabolites in the multiclass diagnostic model. Evaluating the diagnostic model demonstrated its high discriminative ability and accuracy. This study revealed metabolic pathway perturbations at different stages of coronary heart disease, and a precise multiclass diagnostic model was established based on these findings. This study provides new insights and tools for the early diagnosis and treatment of coronary heart disease.

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“…This sampling design has been described and used in prior REGARDS studies. 11,[14][15][16][17][18] In this analysis, participants who were lost to follow-up, had a history of stroke at the time of enrollment, or had no plasma available for metabolite measurements were excluded. We also excluded participants with hemorrhagic stroke and those without a record of stroke type.…”

Section: Study Design and Populationmentioning

confidence: 99%

“…13 Additionally, we demonstrated that a plasma metabolite, gluconic acid, linked hypertension, and incident ischemic stroke, specifically among Black adults, and was also associated with socioeconomic and behavioral measures. 14 These studies suggest the potential of the plasma metabolites, which may serve as biomarkers to reflect the lifestyle or health behaviors that impact the risk of stroke. Because LS7 is a parameter that reflects vascular health, we hypothesize that there are plasma metabolites that are associated with LS7 and link the LS7 with stroke risk.…”

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confidence: 99%

Plasma Metabolites and Life’s Simple 7 in REGARDS

Kijpaisalratana,

Ament,

Patki

et al. 2024

Stroke

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BACKGROUND: The American Heart Association’s Life’s Simple 7 (LS7) is a health metric that captures important factors associated with cardiovascular and cerebrovascular health. Previous studies highlight the potential of plasma metabolites to serve as a marker for lifestyle and health behavior that could be a target for stroke prevention. The objectives of this study were to identify metabolites that were associated with LS7 and incident ischemic stroke and mediate the relationship between the two. METHODS: Targeted metabolomic profiling of 162 metabolites by liquid chromatography–tandem mass spectrometry was used to identify candidate metabolites in a stroke case–cohort nested within the REGARDS study (Reasons for Geographic and Racial Differences in Stroke). Weighted linear regression and weighted Cox proportional hazard models were used to identify metabolites that were associated with LS7 and incident ischemic stroke, respectively. Effect measures were based on a 1-SD change in metabolite level. Metabolite mediators were examined using inverse odds ratio weighting mediation analysis. RESULTS: The study comprised 1075 ischemic stroke cases and 968 participants in the random cohort sample. Three out of 162 metabolites were associated with the overall LS7 score including guanosine (β, −0.46 [95% CI, −0.65 to −0.27]; P =2.87×10 −6 ), cotinine (β, −0.49 [95% CI, −0.70 to −0.28]; P =7.74×10 −6 ), and acetylneuraminic acid (β, −0.59 [95% CI, −0.77 to −0.42]; P =4.29×10 −11 ). Guanosine (hazard ratio, 1.47 [95% CI, 1.31–1.65]; P =6.97×10 −11 ), cotinine (hazard ratio, 1.30 [95% CI, 1.16–1.44]; P =2.09×10 −6 ), and acetylneuraminic acid (hazard ratio, 1.29 [95% CI, 1.15–1.45]; P =9.24×10 −6 ) were associated with incident ischemic stroke. The mediation analysis identified guanosine (27% mediation, indirect effect; P =0.002), cotinine (30% mediation, indirect effect; P =0.004), and acetylneurminic acid (22% mediation, indirect effect; P =0.041) partially mediated the relationship between LS7 and ischemic stroke. CONCLUSIONS: We identified guanosine, cotinine, and acetylneuraminic acid that were associated with LS7, incident ischemic stroke, and mediated the relationship between LS7 and ischemic stroke.

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Association of Circulating Metabolites With Racial Disparities in Hypertension and Stroke in the REGARDS Study

Cited by 9 publications

References 38 publications

Trimethylamine N-Oxide and White Matter Hyperintensity Volume Among Patients With Acute Ischemic Stroke

Trimethylamine N-Oxide and White Matter Hyperintensity Volume Among Patients With Acute Ischemic Stroke

Plasma Metabolic Profiling and Multiclass Diagnostic Model Development for Stable Angina Pectoris and Acute Myocardial Infarction

Plasma Metabolites and Life’s Simple 7 in REGARDS

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