This Article Figures Only Full Text Full Text (PDF) All Versions of this Article: j.jacc.2005.03.068v1 46/2/344    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (24) Citing Articles via Google Scholar Google Scholar Articles by Broadley, A. J.M. Articles by Frenneaux, M. P. Search for Related Content PubMed PubMed Citation Articles by Broadley, A. J.M. Articles by Frenneaux, M. P.

CLINICAL RESEARCH: CARDIOVASCULAR EFFECTS OF STRESS

Inhibition of Cortisol Production With Metyrapone Prevents Mental Stress-Induced Endothelial Dysfunction and Baroreflex Impairment

Andrew J.M. Broadley, MRCP^_*, Ania Korszun, MRCPsych, Eltigani Abdelaal, MRCP, Valentina Moskvina, PhD^||, Christopher J.H. Jones, FRCP^¶, Gerard B. Nash, PhD, Clare Ray, PhD, John Deanfield, FRCP^# and Michael P. Frenneaux, FRCP, FACC^,_*

^_* Heart and Lung Unit, Torbay Hospital, Torquay, United Kingdom
Bart’s and the London Queen Mary College of Medicine and Dentistry, London, United Kingdom
Department of Cardiovascular Medicine, University of Birmingham Medical School, Birmingham, United Kingdom
Department of Physiology, University of Birmingham Medical School, Birmingham, United Kingdom
^|| Department of Psychological Medicine, University of Wales College of Medicine, Cardiff, Wales, United Kingdom
^¶ Department of Cardiology, University of Wales College of Medicine, Cardiff, Wales, United Kingdom
^# Department of Cardiology, Great Ormond Street Hospital for Children, London, United Kingdom

Manuscript received January 24, 2005; revised manuscript received March 21, 2005, accepted March 29, 2005.

^_* Reprint requests and correspondence: Prof. Michael P. Frenneaux, Department of Cardiovascular Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom (Email: M.P.Frenneaux{at}bham.ac.uk).

OBJECTIVES: This study was designed to investigate the role of cortisol in stress-induced endothelial dysfunction and impaired baroreflex sensitivity (BRS) by blocking cortisol production with metyrapone before subjecting healthy volunteers to mental stress.

BACKGROUND: Mental stress raises cortisol levels and is associated with increased coronary heart disease (CHD) morbidity and mortality, especially from sudden cardiac death. It also causes endothelial dysfunction and impaired BRS.

METHODS: We measured brachial artery flow-mediated dilation (FMD), a measure of endothelial function, and BRS in 36 subjects without CHD risk factors who were then randomized in a double-blind fashion to oral metyrapone 750 mg x 2 or placebo. Five hours later we subjected subjects to mental stress and then remeasured endothelial function and BRS.

RESULTS: Prestress cortisol levels were significantly higher in the placebo group at 270.5 (30.9) nmol/l versus 89.1 (11.8) nmol/l (p = 0.01), and the increase with stress was higher at 57.9 (17.9) nmol/l versus 11.2 (2.2) nmol/l (p < 0.001). In the placebo group, compared to baseline, FMD and BRS fell significantly from 4.5% (0.7%) to 1.4% (1.1%) (p = 0.02) and 21.4 (2.3) ms/mm Hg to 16.3 (1.5) ms/mm Hg (p = 0.04), respectively. In the metyrapone group, FMD and BRS were unchanged from baseline: 4.3% (0.9%) versus 5.1% (0.8%) (p = 0.48) and 26.4 (2.9) ms/mm Hg versus 24.9 (2.6) ms/mm Hg (p = 0.62), respectively. Analysis of covariation showed a significant effect of metyrapone on change in both FMD (p = 0.009) and BRS (p = 0.024).

CONCLUSIONS: Stress-related endothelial dysfunction and BRS impairment can be prevented by blocking cortisol production with metyrapone, demonstrating a direct or facilitative role for cortisol in these phenomena and suggesting mechanisms by which stress contributes to CHD and sudden cardiac death.

Abbreviations and Acronyms   BRS = baroreflex sensitivity   CHD = coronary heart disease   ECG = electrocardiogram   ET = endothelin   FMD = flow-mediated dilation   GTN = glyceryl trinitrate   GTNMD = glyceryl trinitrate-mediated endothelium-independent dilation   HUVEC = human umbilical vein endothelial cell   NO = nitric oxide   NOS = nitric oxide synthase

This article has been cited by other articles:

				M. Hamer, K. O'Donnell, A. Lahiri, and A. Steptoe Salivary cortisol responses to mental stress are associated with coronary artery calcification in healthy men and women Eur. Heart J., September 10, 2009; (2009) ehp386v1. [Abstract] [Full Text] [PDF]

				C. Vlachopoulos, P. Xaplanteris, N. Alexopoulos, K. Aznaouridis, C. Vasiliadou, K. Baou, E. Stefanadi, and C. Stefanadis Divergent Effects of Laughter and Mental Stress on Arterial Stiffness and Central Hemodynamics Psychosom Med, May 1, 2009; 71(4): 446 - 453. [Abstract] [Full Text] [PDF]

				K. M Dickinson, J. B Keogh, and P. M Clifton Effects of a low-salt diet on flow-mediated dilatation in humans Am. J. Clinical Nutrition, February 1, 2009; 89(2): 485 - 490. [Abstract] [Full Text] [PDF]

				G. J. Molloy, L. Perkins-Porras, P. C. Strike, and A. Steptoe Type-D Personality and Cortisol in Survivors of Acute Coronary Syndrome Psychosom Med, October 1, 2008; 70(8): 863 - 868. [Abstract] [Full Text] [PDF]

				R. G. Barr, S. Mesia-Vela, J. H. M. Austin, R. C. Basner, B. M. Keller, A. P. Reeves, D. Shimbo, and L. Stevenson Impaired Flow-mediated Dilation Is Associated with Low Pulmonary Function and Emphysema in Ex-smokers: The Emphysema and Cancer Action Project (EMCAP) Study Am. J. Respir. Crit. Care Med., December 15, 2007; 176(12): 1200 - 1207. [Abstract] [Full Text] [PDF]

				D. L. Daubert and V. L. Brooks Nitric oxide impairs baroreflex gain during acute psychological stress Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2007; 292(2): R955 - R961. [Abstract] [Full Text] [PDF]

				H. B. van Wezel, C. J. Zuurbier, E. de Jonge, E. W. C. M. van Dam, J. van Dijk, E. Endert, B. A. de Mol, and E. Fliers Differential Effects of a Perioperative Hyperinsulinemic Normoglycemic Clamp on the Neurohumoral Stress Response during Coronary Artery Surgery J. Clin. Endocrinol. Metab., October 1, 2006; 91(10): 4144 - 4153. [Abstract] [Full Text] [PDF]

				T. Hizume, K. Morikawa, A. Takaki, K. Abe, K. Sunagawa, M. Amano, K. Kaibuchi, C. Kubo, and H. Shimokawa Sustained Elevation of Serum Cortisol Level Causes Sensitization of Coronary Vasoconstricting Responses in Pigs In Vivo: A Possible Link Between Stress and Coronary Vasospasm Circ. Res., September 29, 2006; 99(7): 767 - 775. [Abstract] [Full Text] [PDF]

				K. Matthews, J. Schwartz, S. Cohen, and T. Seeman Diurnal Cortisol Decline is Related to Coronary Calcification: CARDIA Study. Psychosom Med, September 1, 2006; 68(5): 657 - 661. [Abstract] [Full Text] [PDF]

				A. J.M. Broadley, A. Korszun, E. Abdelaal, V. Moskvina, J. Deanfield, C. J.H. Jones, and M. P. Frenneaux Metyrapone Improves Endothelial Dysfunction in Patients With Treated Depression J. Am. Coll. Cardiol., July 4, 2006; 48(1): 170 - 175. [Abstract] [Full Text] [PDF]

				K Raza, D M Carruthers, R Stevens, A D Filer, J N Townend, and P A Bacon Infliximab leads to a rapid but transient improvement in endothelial function in patients with primary systemic vasculitis Ann Rheum Dis, July 1, 2006; 65(7): 946 - 948. [Abstract] [Full Text] [PDF]

				D. Lucini, G. Di Fede, G. Parati, and M. Pagani Impact of Chronic Psychosocial Stress on Autonomic Cardiovascular Regulation in Otherwise Healthy Subjects Hypertension, November 1, 2005; 46(5): 1201 - 1206. [Abstract] [Full Text] [PDF]