Dimethylguanidino Valerate: A Lifestyle‐Related Metabolite Associated With Future Coronary Artery Disease and Cardiovascular Mortality

Background Identification of lifestyle modifiable metabolic pathways related to cardiometabolic disease risk is essential for improvement of primary prevention in susceptible individuals. It was recently shown that plasma dimethylguanidino valerate (DMGV) levels are associated with incident type 2 diabetes mellitus. Our aims were to investigate whether plasma DMGV is related to risk of future coronary artery disease and with cardiovascular mortality and to replicate the association with type 2 diabetes mellitus and pinpoint candidate lifestyle interventions susceptible to modulate DMGV levels. Methods and Results Plasma DMGV levels were measured using liquid chromatography‐mass spectrometry in a total of 5768 participants from the MDC (Malmö Diet and Cancer Study—Cardiovascular Cohort), MPP (Malmö Preventive Project), and MOS (Malmö Offspring Study). Dietary intake assessment was performed in the MOS. Baseline levels of DMGV associated with incident coronary artery disease in both the MDC (hazard ratio=1.29; CI=1.16–1.43; P<0.001) and MPP (odds ratio=1.25; CI=1.08–1.44; P=2.4e‐3). In the MDC, DMGV was associated with cardiovascular mortality and incident coronary artery disease, independently of traditional risk factors. Furthermore, the association between DMGV and incident type 2 diabetes mellitus was replicated in both the MDC (hazard ratio=1.83; CI=1.63–2.05; P<0.001) and MPP (odds ratio=1.65; CI=1.38–1.98; P<0.001). Intake of sugar‐sweetened beverages was associated with increased levels of DMGV, whereas intake of vegetables and level of physical activity was associated with lower DMGV. Conclusions We discovered novel independent associations between plasma DMGV and incident coronary artery disease and cardiovascular mortality, while replicating the previously reported association with incident type 2 diabetes mellitus. Additionally, strong associations with sugar‐sweetened beverages, vegetable intake, and physical activity suggest the potential to modify DMGV levels using lifestyle interventions.

[1]  C. Bouchard,et al.  Association of Dimethylguanidino Valeric Acid With Partial Resistance to Metabolic Health Benefits of Regular Exercise. , 2019, JAMA cardiology.

[2]  P. Almgren,et al.  Connection Between BMI-Related Plasma Metabolite Profile and Gut Microbiota , 2018, The Journal of clinical endocrinology and metabolism.

[3]  David S. Wishart,et al.  HMDB 4.0: the human metabolome database for 2018 , 2017, Nucleic Acids Res..

[4]  F. Hu,et al.  Use of Metabolomics in Improving Assessment of Dietary Intake. , 2018, Clinical chemistry.

[5]  R. Vasan,et al.  Dimethylguanidino valeric acid is a marker of liver fat and predicts diabetes , 2017, The Journal of clinical investigation.

[6]  T. Lehtimäki,et al.  The biomarker and causal roles of homoarginine in the development of cardiometabolic diseases: an observational and Mendelian randomization analysis , 2017, Scientific Reports.

[7]  B. Hedblad,et al.  Comparison of a web-based food record tool and a food-frequency questionnaire and objective validation using the doubly labelled water technique in a Swedish middle-aged population , 2016, Journal of Nutritional Science.

[8]  S. Nybacka,et al.  Validity of a web-based dietary questionnaire designed especially to measure the intake of phyto-oestrogens , 2016, Journal of Nutritional Science.

[9]  P. Almgren,et al.  Postprandial Levels of Branch Chained and Aromatic Amino Acids Associate with Fasting Glycaemia , 2016, Journal of amino acids.

[10]  O. Melander,et al.  Genetic vasopressin 1b receptor variance in overweight and diabetes mellitus , 2015, European journal of endocrinology.

[11]  Daniel F. Freitag,et al.  Asymmetric Dimethylarginine and Cardiovascular Risk: Systematic Review and Meta-Analysis of 22 Prospective Studies , 2015, Journal of the American Heart Association.

[12]  G. von Heijne,et al.  Tissue-based map of the human proteome , 2015, Science.

[13]  S. Lentz,et al.  AGXT2: a promiscuous aminotransferase. , 2014, Trends in pharmacological sciences.

[14]  C. Ayers,et al.  Homoarginine and Cardiovascular Outcome in the Population-Based Dallas Heart Study , 2014, Arteriosclerosis, thrombosis, and vascular biology.

[15]  John P. Overington,et al.  An atlas of genetic influences on human blood metabolites , 2014, Nature Genetics.

[16]  Chad A. Cowan,et al.  β-Aminoisobutyric acid induces browning of white fat and hepatic β-oxidation and is inversely correlated with cardiometabolic risk factors. , 2014, Cell metabolism.

[17]  G A Nagana Gowda,et al.  Biomarker Discovery and Translation in Metabolomics. , 2013, Current Metabolomics.

[18]  P. O’Reilly,et al.  Long-term Leisure-time Physical Activity and Serum Metabolome , 2013, Circulation.

[19]  R. Maas,et al.  In vivo evidence that Agxt2 can regulate plasma levels of dimethylarginines in mice. , 2013, Biochemical and biophysical research communications.

[20]  D. Wishart,et al.  Translational biomarker discovery in clinical metabolomics: an introductory tutorial , 2012, Metabolomics.

[21]  James Tomlinson,et al.  Alanine-Glyoxylate Aminotransferase-2 Metabolizes Endogenous Methylarginines, Regulates NO, and Controls Blood Pressure , 2012, Arteriosclerosis, thrombosis, and vascular biology.

[22]  J. Ludvigsson,et al.  External review and validation of the Swedish national inpatient register , 2011, BMC public health.

[23]  Joshua D. Knowles,et al.  Procedures for large-scale metabolic profiling of serum and plasma using gas chromatography and liquid chromatography coupled to mass spectrometry , 2011, Nature Protocols.

[24]  D. Murry,et al.  Human Alanine-Glyoxylate Aminotransferase 2 Lowers Asymmetric Dimethylarginine and Protects from Inhibition of Nitric Oxide Production* , 2009, The Journal of Biological Chemistry.

[25]  M. Pencina,et al.  Novel and conventional biomarkers for prediction of incident cardiovascular events in the community. , 2009, JAMA.

[26]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[27]  E. Feskens,et al.  A critical review of predefined diet quality scores , 2007, British Journal of Nutrition.

[28]  P. Vallance,et al.  Disruption of methylarginine metabolism impairs vascular homeostasis , 2007, Nature Medicine.

[29]  J. Neaton,et al.  Diabetes, Other Risk Factors, and 12-Yr Cardiovascular Mortality for Men Screened in the Multiple Risk Factor Intervention Trial , 1993, Diabetes Care.