Background/Aims: Endogenous Cushing's syndrome is associated with a higher risk of cardiovascular morbidity and mortality. Previous literature suggested multiple possible links by which hypercortisolism may alter the autonomic control of cardiovascular functions. We investigated the impact of chronic endogenous hypercortisolism on the autonomic regulation of cardiac functions by short-term heart rate variability analysis. Methods: Eighteen patients with endogenous Cushing's syndrome and 20 age-, gender- and BMI-matched controls participated in the study. ECG signal was acquired in lead II configuration for 5 min and heart rate variability assessment was made in both time and frequency domain using the extracted RR interval data. Results: All time and frequency domain measures of heart rate variability were significantly (p < 0.05) lower in the patient group compared to the control group. The patient group had an altered sympathovagal balance with low frequency/high frequency band ratio significantly higher than the control group [1.857 (0.6747-2.610) vs. 0.8581 (0.4779-1.352); p = 0.0253]. A significant negative correlation was obtained between normalized high frequency power of heart rate variability and basal cortisol levels (r = -0.6594; p = 0.0029). Multiple linear regression analysis identified age, disease duration (in months), basal cortisol levels and systolic blood pressure as independent predictors of normalized high frequency power. Conclusion: Findings of the study clearly portrayed the diminished autonomic modulation of heart rate in endogenous Cushing's syndrome and its possible relationship with hypercortisolism as the main causative factor. Diminished heart rate variability may be an indicator of the increased risk of cardiac mortality in these patients.

1.
Etxabe J, Vazquez JA: Morbidity and mortality in Cushing's disease: an epidemiological approach. Clin Endocrinol (Oxf) 1994;40:479-484.
2.
Steffensen C, Bak AM, Rubeck KZ, Jørgensen JO: Epidemiology of Cushing's syndrome. Neuroendocrinology 2010;92(suppl 1):1-5.
3.
De Leo M, Pivonello R, Auriemma RS, Cozzolino A, Vitale P, Simeoli C, et al: Cardiovascular disease in Cushing's syndrome: heart versus vasculature. Neuroendocrinology 2010;92(suppl 1):50-54.
4.
Pivonello R, Faggiano A, Lombardi G, Colao A: The metabolic syndrome and cardiovascular risk in Cushing's syndrome. Endocrinol Metab Clin North Am 2005;34:327-339, viii.
5.
Cicala MV, Mantero F: Hypertension in Cushing's syndrome: from pathogenesis to treatment. Neuroendocrinology 2010;92(suppl 1):44-49.
6.
Trementino L, Arnaldi G, Appolloni G, Daidone V, Scaroni C, Casonato A, et al: Coagulopathy in Cushing's syndrome. Neuroendocrinology 2010;92(suppl 1):55-59.
7.
Valassi E, Biller BM, Klibanski A, Misra M: Adipokines and cardiovascular risk in Cushing's syndrome. Neuroendocrinology 2012;95:187-206.
8.
Jyotsna VP, Naseer A, Sreenivas V, Gupta N, Deepak KK: Effect of Cushing's syndrome - endogenous hypercortisolemia on cardiovascular autonomic functions. Auton Neurosci 2011;160:99-102.
9.
Fallo F, Maffei P, Dalla Pozza A, Carli M, Della Mea P, Lupia M, et al: Cardiovascular autonomic function in Cushing's syndrome. J Endocrinol Invest 2009;32:41-45.
10.
Takahashi H, Takeda K, Ashizawa H, Inoue A, Yoneda S, Yoshimura M, et al: Centrally induced cardiovascular and sympathetic responses to hydrocortisone in rats. Am J Physiol 1983;245:H1013-H1018.
11.
Tam SH, Kelly JJ, Williamson PM, Whitworth JA: Reflex sympathetic function in cortisol-induced hypertension in humans. Clin Exp Hypertens 1997;19:479-493.
12.
Dodt C, Keyser B, Mölle M, Fehm HL, Elam M: Acute suppression of muscle sympathetic nerve activity by hydrocortisone in humans. Hypertension 2000;35:758-763.
13.
Scheuer DA, Bechtold AG: Glucocorticoids modulate baroreflex control of heart rate in conscious normotensive rats. Am J Physiol Regul Integr Comp Physiol 2002;282:R475-R483.
14.
Bechtold AG, Scheuer DA: Glucocorticoids act in the dorsal hindbrain to modulate baroreflex control of heart rate. Am J Physiol Regul Integr Comp Physiol 2006;290:R1003-R1011.
15.
Scheuer DA, Mifflin SW: Glucocorticoids modulate baroreflex control of renal sympathetic nerve activity. Am J Physiol Regul Integr Comp Physiol 2001;280:R1440-R1449.
16.
Mannelli M, Lanzillotti R, Pupilli C, Ianni L, Conti A, Serio M: Adrenal medulla secretion in Cushing's syndrome. J Clin Endocrinol Metab 1994;78:1331-1335.
17.
Lahiri MK, Kannankeril PJ, Goldberger JJ: Assessment of autonomic function in cardiovascular disease: physiological basis and prognostic implications. J Am Coll Cardiol 2008;51:1725-1733.
18.
Cohen MA, Taylor JA: Short-term cardiovascular oscillations in man: measuring and modelling the physiologies. J Physiol (Lond) 2002;542:669-683.
19.
Malpas SC: Neural influences on cardiovascular variability: possibilities and pitfalls. Am J Physiol Heart Circ Physiol 2002;282:H6-H20.
20.
Heart rate variability: standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Circulation 1996;93:1043-1065.
21.
Tsuji H, Venditti FJ Jr, Manders ES, Evans JC, Larson MG, Feldman CL, et al: Reduced heart rate variability and mortality risk in an elderly cohort. The Framingham Heart Study. Circulation 1994;90:878-883.
22.
Tsuji H, Larson MG, Venditti FJ Jr, Manders ES, Evans JC, Feldman CL, et al: Impact of reduced heart rate variability on risk for cardiac events. The Framingham Heart Study. Circulation 1996;94:2850-2855.
23.
Bigger JT Jr, Fleiss JL, Steinman RC, Rolnitzky LM, Kleiger RE, Rottman JN: Frequency domain measures of heart period variability and mortality after myocardial infarction. Circulation 1992;85:164-171.
24.
Nieman LK, Biller BMK, Findling JW, Newell-Price J, Savage MO, Stewart PM, et al: The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2008;93:1526-1540.
25.
Lombardi F, Malliani A, Pagani M, Cerutti S: Heart rate variability and its sympatho-vagal modulation. Cardiovasc Res 1996;32:208-216.
26.
Liao D, Carnethon M, Evans GW, Cascio WE, Heiss G: Lower heart rate variability is associated with the development of coronary heart disease in individuals with diabetes: the atherosclerosis risk in communities (ARIC) study. Diabetes 2002;51:3524-3531.
27.
Clayton RN: Mortality in Cushing's disease. Neuroendocrinology 2010;92(suppl 1):71-76.
28.
Whitworth JA, Mangos GJ, Kelly JJ: Cushing, cortisol, and cardiovascular disease. Hypertension 2000;36:912-916.
29.
Whitworth JA, Williamson PM, Mangos G, Kelly JJ: Cardiovascular consequences of cortisol excess. Vasc Health Risk Manag 2005;1:291-299.
30.
Chandran DS, Jaryal AK, Jyotsna VP, Deepak KK: Impaired endothelium mediated vascular reactivity in endogenous Cushing's syndrome. Endocr J 2011;58:789-799.
31.
Scherrer U, Sartori C: Defective nitric oxide synthesis: a link between metabolic insulin resistance, sympathetic overactivity and cardiovascular morbidity. Eur J Endocrinol 2000;142:315-323.
32.
Chowdhary S, Townend JN: Role of nitric oxide in the regulation of cardiovascular autonomic control. Clin Sci 1999;97:5-17.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.