Metabolomic profiling identifies novel metabolites associated with cardiac dysfunction

• Published in: Scientific reports 2024-09, Vol.14 (1), p.20694-11, Article 20694
• Main Authors: Culler, Kasen L., Sinha, Arjun, Filipp, Mallory, Giro, Pedro, Allen, Norrina B., Taylor, Kent D., Guo, Xiuqing, Thorp, Ed, Freed, Benjamin H., Greenland, Philip, Post, Wendy S., Bertoni, Alain, Herrington, David, Gao, Chen, Wang, Yibin, Shah, Sanjiv J., Patel, Ravi B.
• Format: Article
• Language: English
• Subjects: 692/4019; 692/4019/592/2727; 692/4019/592/75/230; Aged; Aged, 80 and over; Amino acids; Arteriosclerosis; Biomarkers - blood; Brain natriuretic peptide; Cardiac structure; Carnitine; Comorbidity; Congestive heart failure; Diabetes mellitus; Echocardiography; Female; Genetic analysis; Genetic diversity; Genetic variance; Genetics; Glucose metabolism; Heart diseases; Heart failure; Heart Failure - genetics; Heart Failure - metabolism; Humanities and Social Sciences; Humans; Inositol; Inositol - metabolism; Male; Mannose; Metabolic pathways; Metabolism; Metabolites; Metabolome; Metabolomics; Metabolomics - methods; Middle Aged; multidisciplinary; Natriuretic peptide; Natriuretic Peptide, Brain - blood; Natriuretic Peptide, Brain - metabolism; Peptide Fragments - blood; Peptides; Science; Science (multidisciplinary); Stroke Volume; Structure-function relationships
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-71329-y

Metabolic comorbidities, such as obesity and diabetes, are associated with subclinical alterations in both cardiac structure/function and natriuretic peptides prior to the onset of heart failure (HF). Despite this, the exact metabolic pathways of cardiac dysfunction which precede HF are not well-defined. Among older individuals without HF in the Multi-Ethnic Study of Atherosclerosis (MESA), we evaluated the associations of 47 circulating metabolites measured by 1 H-NMR with echocardiographic measures of cardiac structure and function. We then evaluated associations of significant metabolites with circulating N-terminal pro-B-type natriuretic peptide (NT-proBNP). In a separate cohort, we evaluated differences between top metabolites in patients with HF with preserved ejection fraction (HFpEF) and comorbidity-matched controls. Genetic variants associated with top metabolites (mQTLs) were then related to echocardiographic measures and NT-proBNP. Among 3440 individuals with metabolic and echocardiographic data in MESA (62 ± 10 years, 52% female, 38% White), 10 metabolites broadly reflective of glucose and amino acid metabolism were associated with at least 1 measure of cardiac structure or function. Of these 10 metabolites, 4 (myo-inositol, glucose, dimethylsulfone, carnitine) were associated with higher NT-proBNP and 2 (d-mannose, acetone) were associated with lower NT-proBNP. In a separate cohort, patients with HFpEF had higher circulating myo-inositol levels compared with comorbidity-matched controls. Genetic analyses revealed that 1 of 6 known myo-inositol mQTLs conferred risk of higher NT-proBNP. In conclusion, metabolomic profiling identifies several novel metabolites associated with cardiac dysfunction in a cohort at high risk for HF, revealing pathways potentially relevant to future HF risk.