Skip to main content

Advertisement

SpringerLink
Log in

Metabolomics analysis reveals insights into biochemical mechanisms of mental stress-induced left ventricular dysfunction

  • Original Article
  • Published:
Metabolomics Aims and scope Submit manuscript

Abstract

Mental stress induced left ventricular dysfunction (LVD) has been associated with a greater risk of adverse events in coronary heart disease (CHD) patients independent of conventional risk indicators. The underlying biochemical mechanisms of this cardiovascular condition are poorly understood. Our objective was to use metabolomics technology to identify biochemical changes that co-occur with mental stress-induced LVD in patients with clinically stable CHD. Participants were adult CHD patients who were recruited for mental stress-induced myocardial ischemia screening. For this study, we randomly selected 30 patients representing the extremes of the mental stress-induced left ventricular ejection fraction (LVEF) change distribution; 15 who showed LVD (i.e. LVEF reduction ≥5) and 15 who showed a normal left ventricular response (NLVR; i.e. a LVEF increase of ≥5) to three mental stressors. An electrochemistry based metabolomics platform was used to profile pre- and post-stress serum samples yielding data for 22 known compounds, primarily within the tyrosine, tryptophan, purine and methionine pathways. There were significant stress-induced changes in several compounds. A comparison between the NLVR and LVD groups showed significant effects for kynurenine (p = .036, N-acetylserotonin (p = .054), uric acid (p = .015), tyrosine (p = .019) and a trend for methionine (p = .065); the NLVR group showed a significantly greater stress-induced reduction in all of those compounds compared to the LVD group. Many of these biochemicals have been implicated in other stress-related phenomena and are plausible candidates for mechanisms underlying LVD in response to mental stress.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Babyak, M. A., Blumenthal, J. A., Hinderliter, A., et al. (2010). Prognosis after change in left ventricular ejection fraction during mental stress testing in patients with stable coronary artery disease. American Journal of Cardiology, 105, 25–28.

    Article  PubMed Central  PubMed  Google Scholar 

  • Bendheim, P. E., Poeggeler, B., Neria, E., Ziv, V., Pappolla, M. A., & Chain, D. G. (2002). Development of indole-3-propionic acid (OXIGON) for Alzheimer’s disease. Journal of Molecular Neuroscience, 19(1–2), 213–217.

    Article  CAS  PubMed  Google Scholar 

  • Bogdanov, M., et al. (2008). Metabolomic profiling to develop blood biomarkers for Parkinson’s disease. Brain, 31, 389–396.

    Article  Google Scholar 

  • Boyle, S. H., Samad, Z., Becker, R. C., Williams, R., Kuhn, C., Ortel, T. L., Kuchibhatla, M., Prybol, K., Rogers, J., O’Connor, C., Velazquez, E. J., Jiang, W. (2013). Depressive symptoms and mental stress-induced myocardial ischemia in patients with coronary heart disease. Psychosomatic Medicine, 75(9), 822–831.

  • Cantoni, G. L., Mudd, S. H., & Andreoli, V. (1989). Affective disorders and S-adenosylmethionine: A new hypothesis. Trends in Neurosciences, 12, 319–324.

    Article  CAS  PubMed  Google Scholar 

  • Catena-Dell’Osso, M., Marazziti, D., Rotella, F., Bellantuono, C. (2012). Emerging target for the pharmacological treatment of depression: focus on melatonergic system. Current Medicinal Chemistry, 19(3), 428–37.

  • Coppola, A., Wenner, B. R., Ilkayeva, O., Stevens, R. D., Maggioni, M., Slotkin, T. A., Levin, E. D., Newgard, C. B. (2013). Branched-chain amino acids alter neurobehavioral function in rats. American Journal of Physiology—Endocrinology and Metabolism, 304(4), E405–13.

  • de Winter, J. F. C., Dodou, D., Wieringa, P. A. (2009). Exploratory factor analysis with small sample sizes. Multivariate Behavioral Research, 44(2), 147–181.

  • Dubocovich, M. L., Delagrange, P., Krause, D. N., Sugden, D., Cardinali, D. P., & Olcese, J. (2010). International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, classification, and pharmacology of G protein-coupled melatonin receptors. Pharmacological Reviews, 62(3), 343–380.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Edmondson, D., Newman, J. D., Whang, W., Davidson, K. W. (2013). Emotional triggers in myocardial infarction: do they matter?. European Heart Journal, 34(4), 300–6.

  • Goldberg, A. D., Becker, L. C., Bonsall, R., et al. (1996). Ischemic, hemodynamic, and neurohormonal responses to mental and exercise stress. Experience from the Psychophysiological Investigations of Myocardial Ischemia Study (PIMI). Circulation, 94(10), 2402–2409.

    Article  CAS  PubMed  Google Scholar 

  • Hemingway, H., & Marmot, M. (1999). Evidence based cardiology: Psychosocial factors in the aetiology and prognosis of coronary heart disease. Systematic review of prospective cohort studies. BMJ, 318, 1460–1467.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ji, Y., Hebbring, S., Zhu, H., et al. (2011). Glycine and a glycine dehydrogenase (GLDC) SNP as citalopram/escitalopram response biomarkers in depression: Pharmacometabolomics-informed pharmacogenomics. Clinical Pharmacology and Therapeutics, 89(1), 97–104.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jiang, W., Babyak, M., Krantz, D. S., et al. (1996). Mental stress-induced myocardial ischemia and cardiac events. Jama-J Am Med Assoc, 275, 1651–1656.

    Article  CAS  Google Scholar 

  • Jiang, W., Babyak, M. A., Rozanski, A., et al. (2003). Depression and increased myocardial ischemic activity in patients with ischemic heart disease. American Heart Journal, 146, 55–61.

    Article  PubMed  Google Scholar 

  • Jiang, W., Velazquez, E. J., Samad, Z., Kuchibhatla, M., Martsberger, C., Rogers, J., et al. (2012). Responses of mental stress-induced myocardial ischemia to escitalopram treatment: background, design, and method for the responses of mental stress induced myocardial ischemia to escitalopram treatment trial. American Heart Journal, 163(1), 20–26.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kaddurah-Daouk, R., Yuan, P., Boyle, S. H., Matson, W., Wang, Z., Zeng, Z. B., Zhu, H., Dougherty, G. G., Yao, J. K., Chen, G., Guitart, X., Carlson, P. J., Neumeister, A., Zarate, C., Krishnan, R. R., Manji, H. K., Drevets, W. (2012). Cerebrospinal fluid metabolome in mood disorders-remission state has a unique metabolic profile. Science Report, 2, 1–10.

  • Kagan, B. L., Sultzer, D. L., Rosenlicht, N., & Gerner, R. H. (1990). Oral S-adenosylmethionine in depression: a randomized, double-blind, placebo-controlled trial. American Journal of Psychiatry, 147, 591–595.

    Article  CAS  PubMed  Google Scholar 

  • Kanellis, J., & Kang, D. H. (2005). Uric acid as a mediator of endothelial dysfunction, inflammation, and vascular disease. Seminars in Nephrology, 25(1), 39–42.

    Article  CAS  PubMed  Google Scholar 

  • Krantz, D. S., Santiago, H. T., Kop, W. J., et al. (1999). Prognostic value of mental stress testing in coronary artery disease. American Journal of Cardiology, 84, 1292–1297.

    Article  CAS  PubMed  Google Scholar 

  • Kristal, B. S., Vigneau-Callahan, K., & Matson, W. R. (2002). Simultaneous analysis of multiple redox-active metabolites from biological matrices. Methods in Molecular Biology, 186, 185–194.

    CAS  PubMed  Google Scholar 

  • Kuroda, T., Kuwabara, Y., Watanabe, S., et al. (2000). Effect of mental stress on left ventricular ejection fraction and its relationship to the severity of coronary artery disease. European Journal of Nuclear Medicine, 27, 1760–1767.

    Article  CAS  PubMed  Google Scholar 

  • Kutzing, M., & Firestein, B. L. (2008). Altered uric acid levels and disease states. Journal of Pharmacology and Experimental Therapeutics, 324, 1–7.

    Article  CAS  PubMed  Google Scholar 

  • Lett, H. S., Blumenthal, J. A., Babyak, M. A., et al. (2004). Depression as a risk factor for coronary artery disease: Evidence, mechanisms, and treatment. Psychosomatic Medicine, 66, 305–315.

    PubMed  Google Scholar 

  • Lokhandwala, M. F., & Barrett, R. J. (1982). Cardiovascular dopamine receptors: Physiological, pharmacological implications. Journal of Autonomic Pharmacology, 2(3), 189–215.

    Article  CAS  PubMed  Google Scholar 

  • Maren Depke, M., Gerhard Fusch, G., Grazyna Domanska, G., Robert Geffers, R., Uwe Vo¨lker, U., Christine Schuett, C., Cornelia Kiank, C. (2008). Hypermetabolic Syndrome as a Consequence of repeated psychological stress in mice. Endocrinology, 149(6), 2714–2723.

  • Matson, W., Langials, P., Volicer, L., Gamache, P., Bird, E., & Mark, K. (1984). N-electrode three dimensional liquid chromatography with electrochemical detection for determination of neurotransmitters. Clinical Chemistry, 30, 1477–1488.

    CAS  PubMed  Google Scholar 

  • McCall, R. B., & Clement, M. E. (1994). Role of serotonin1A and serotonin2 receptors in the central regulation of the cardiovascular system. Pharmacological Reviews, 46, 231–243.

    CAS  PubMed  Google Scholar 

  • Miura, H., Ozaki, N., Sawada, M., Isobe, K., Ohta, T., Nagatsu, T. (2008). A link between stress and depression: shifts in the balance between the kynurenine and serotonin pathways of tryptophan metabolism and the etiology and pathophysiology of depression. Stress, 11(3), 198–209.

  • Oxenkrug, G. F. (1999). Antidepressive and antihypertensive effects of MAO-A inhibition: role of N-acetylserotonin. A review. Journal of Neurobiology, 7, 213–224.

    CAS  Google Scholar 

  • Oxenkrug, G., & Ratner, R. (2012). N-acetylserotonin and aging-associated cognitive impairment and depression. Aging & Disease, 3(4), 330–8.

  • Oxenkrug, G. (2013). Serotonin-kynurenine hypothesis of depression: historical overview and recent developments. Current Drug Targets, 14(5):514–21.

  • Paige, L. A., Mitchell, M. W., Krishnan, K. R., et al. (2007). A preliminary metabolomic analysis of older adults with and without depression. International Journal of Geriatric Psychiatry, 22, 418–423.

    Article  PubMed  Google Scholar 

  • Papakostas, G. I., Alpert, J. E., & Fava, M. (2003). S-adenosyl-methionine in depression: A comprehensive review of the literature. Current Psychiatry Reports, 5(6), 460–466.

    Article  PubMed  Google Scholar 

  • Ramage, A. G., & Villalón, C. M. (2008). 5-Hydroxytryptamine and cardiovascular regulation. Trends in Pharmacological Sciences, 29(9), 472–481.

    Article  CAS  PubMed  Google Scholar 

  • Reiter, R. J., Tan, D. X., & Maldonado, M. D. (2005). Melatonin as an antioxidant: Physiology versus pharmacology. Journal of Pineal Research, 39, 215–216.

    Article  CAS  PubMed  Google Scholar 

  • Rozanski, A., Blumenthal, J. A., & Kaplan, J. (1999). Impact of psychological factors on the pathogenesis of cardiovascular disease and implications for therapy. Circulation, 99, 2192–2217.

    Article  CAS  PubMed  Google Scholar 

  • Rozen, S., Cudkowicz, M. E., Bogdanov, M., Matson, W. R., & Kristal, B. S. (2005). Metabolomic analysis and signatures in motor neuron disease. Metabolomics, 1, 101–108.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Schroeder, C., & Jordan, J. (2012). Norepinephrine transporter function and human cardiovascular disease. American Journal of Physiology Heart and Circulatory Physiology, 303(11), H1273–H1282.

    Article  CAS  PubMed  Google Scholar 

  • Shah, S. H., Sun, J. L., Stevens, R. D., Bain, J. R., Muehlbauer, M. J., Pieper, K. S., et al. (2012). Baseline metabolomic profiles predict cardiovascular events in patients at risk for coronary artery disease. American Heart Journal, 163(5), 844–850.

    Article  CAS  PubMed  Google Scholar 

  • Sheps, D. S., McMahon, R. P., Becker, L., et al. (2002). Mental stress-induced ischemia and all-cause mortality in patients with coronary artery disease—Results from the psychophysiological investigations of myocardial ischemia study. Circulation, 105, 1780–1784.

    Article  PubMed  Google Scholar 

  • Simko, F., & Paulis, L. (2007). Melatonin as a potential antihypertensive treatment. Journal of Pineal Research, 42, 319–322.

    Article  CAS  PubMed  Google Scholar 

  • Soltis, R. P., & DiMicco, J. A. (1992). Hypothalamic excitatory amino acid receptors mediate stress-induced tachycardia in rats. American Journal of Physiology, 262, R689–R697.

    CAS  PubMed  Google Scholar 

  • Steffens, D. C., Wei, J., Krishnan, K. R., Karoly, E. D., Mitchell, M. W., O’Connor, C. M., et al. (2010). Metabolomic differences in heart failure patients with and without major depression. Journal of Geriatric Psychiatry and Neurology, 23(2), 138–146.

    Article  PubMed Central  PubMed  Google Scholar 

  • Stone, T. W. (2001). Kynurenines in the CNS: From endogenous obscurity to therapeutic importance. Progress in Neurobiology, 64, 185–218.

    Article  CAS  PubMed  Google Scholar 

  • Strike, P. C., & Steptoe, A. (2003). Systematic review of mental stress-induced myocardial ischaemia. European Heart Journal, 24, 690–703.

    Article  CAS  PubMed  Google Scholar 

  • Tanu, D. X., Manchester, L. C., Terron, M. P., et al. (2007). One molecule, many derivatives: A never-ending interaction of melatonin with reactive oxygen and reactive nitrogen species? Journal of Pineal Research, 42, 28–42.

    Article  Google Scholar 

  • Teague, C. R., Dhabhar, F. S., Barton, R. H., Beckwith-Hall, B., Powell, J., Cobain, M., et al. (2007). Metabonomic studies on the physiological effects of acute and chronic psychological stress in Sprague–Dawley rats. Journal of Proteome Research, 6(6), 2080–2093.

    Article  CAS  PubMed  Google Scholar 

  • Végh, A., Papp, J. G., Semeraro, C., Fatehi-Hasanabad, Z., & Parratt, J. R. (1998). The dopamine receptor agonist Z1046 reduces ischaemia severity in a canine model of coronary artery occlusion. European Journal of Pharmacology, 344(2–3), 203–213.

    Article  PubMed  Google Scholar 

  • Wang, Z., Klipfell, E., Bennett, B. J., Koeth, R., Levison, B. S., Dugar, B., et al. (2011a). Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature, 472(7341), 57–63.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wang, T. J., Larson, M. G., Vasan, R. S., Cheng, S., Rhee, E. P., McCabe, E., et al. (2011b). Metabolite profiles and the risk of developing diabetes. Nature Medicine, 17(4), 448–453.

    Article  PubMed Central  PubMed  Google Scholar 

  • Wang, Y., Liu, H., McKenzie, G., et al. (2010). Kynurenine is an endothelium-derived relaxing factor produced during inflammation. Nature Medicine, 16, 279–285.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Warda, M., Kim, H. K., Kim, N., Ko, K. S., Rhee, B. D., & Han, J. (2013). A matter of life, death and diseases: Mitochondria from a proteomic perspective. Expert Review of Proteomics, 10(1), 97–111.

    Article  CAS  PubMed  Google Scholar 

  • Watts, S. W., Morrison, S. F., Davis, R. P., & Barman, S. M. (2012). Serotonin and blood pressure regulation. Pharmacological Reviews, 64(2), 359–388.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Xiaoxia Gaoa, X., Zhenga, X., Li, Z., Zhoua, Y., Suna, H., Zhanga, L., Guoa X., Dud, G., Qina, X. (2011). Metabonomic study on chronic unpredictable mild stress and intervention effects of Xiaoyaosan in rats using gas chromatography coupled with mass spectrometry. Journal of Ethnopharmacology, 137, 690– 699,

  • Jiang, W., Samad, Z., Boyle, S., et al. (2013). Prevalence and clinical characteristics of mental stress-induced myocardial ischemia in patients with coronary heart disease. Journal of the American College of Cardiology, 61(7), 714–722.

    Article  PubMed Central  PubMed  Google Scholar 

  • Yao, J. K., Dougherty, G. G., Reddy, R. D., Keshavan, M. S., Monstrose, D. M., Matson, W. R., et al. (2010). Altered interactions of tryptophan metabolites in first-episode neuroleptic-naïve patients with schizophrenia. Molecular Psychiatry, 15(9), 938–953.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yoon, J. H., Ko, C. M., Ahn, Y. S., Park, K. S., Choe, K. H., Yoo, K. J., et al. (1994). Mechanism of decrease in heart rate by peripheral dopaminergic D2-receptors. Yonsei Medical Journal, 35(4), 411–419.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors would also like to thank Ye Zhang, MA, Kevin Prybol, MPH, and Kaitlyn Weinberg for their contributions to the creation of figures and tables for this paper and their assistance in editing the manuscript. The study was funded by National Heart, Lung, and Blood Institute, grant number R01HL085704.

Conflict of interest

Dr. Redford B. Williams reports holding a U.S. patent on the 5HTTLPR L allele for use as a marker of increased cardiovascular risk in stressed persons and is a founder and major stockholder of Williams LifeSkills, Inc. Dr. Velazquez reports receiving research grants from Abbott Laboratories, Evalve, and Ikaria, and consulting fees from Boehringer Ingelheim, Gilead, and Novartis. Dr. O’Connor reports receiving funding from the following: Actelion Pharmaceuticals Ltd., Amgen, Inc., Biscardia, LLC, Cardiology Consulting Associates, Faculty Connection, GE Healthcare, Ikaria, Neurotronik/Interventional Autonomics Corporation, Novella Clinical, Inc., Pfizer Inc., Pozen, and Roche Diagnostics. Dr. Wayne R. Matson is currently Chief Scientist at Counterpoint Health Solutions and is involved in developing patens in disease risk factors based on metabolomics.

Funding Source

The REMIT study was funded by the National Heart Lung and Blood Institute (NHLBI, R01HL085704), Bethesda, Maryland.

Author information

Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Box 3366, Durham, NC, 27710, USA

    Stephen H. Boyle, Redford B. Williams Jr., Jennifer L. Wilson & Wei Jiang

  2. Department of Medicine, Duke University Medical Center, Durham, NC, USA

    Eric J. Velazquez, Zainab Samad, Christopher O’Connor & Wei Jiang

  3. Department of Systems Biochemistry, Counterpoint Health Solutions Inc, Bedford, MA, USA

    Wayne R. Matson, Swati Sharma & Beena Thomas

Authors
  1. Stephen H. Boyle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wayne R. Matson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eric J. Velazquez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zainab Samad
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Redford B. Williams Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Swati Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Beena Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jennifer L. Wilson
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Christopher O’Connor
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Wei Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wei Jiang.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Boyle, S.H., Matson, W.R., Velazquez, E.J. et al. Metabolomics analysis reveals insights into biochemical mechanisms of mental stress-induced left ventricular dysfunction. Metabolomics 11, 571–582 (2015). https://doi.org/10.1007/s11306-014-0718-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11306-014-0718-y

Keywords

Search

Navigation