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J Thorac Cardiovasc Surg 1999;117:365-374
© 1999 Mosby, Inc.

CARDIOTHORACIC TRANSPLANTATION

Acute Brain Death Alters Left Ventricular Myocardial Gene Expression

From the Department of Surgery,^a University of Louisville, Louisville, Ky; the Department of Cardiothoracic Surgery,^b Allegheny University of the Health Sciences, MCP, Hahnemann School of Medicine, Philadelphia, Pa; the Departments of Surgery,^c Physiology,^f and Internal Medicine,^e Medical College of Virginia/Virginia Commonwealth University, Richmond, Va; and the Department of Biological Sciences,^d Mary Washington University, Fredericksburg, Va.

Supported in part by grants from the United States Public Health Service (grant GM3529 [E.R.J.]), from the National Institutes of Health (grant HL26302 [A.S.W.]), and from the American Heart Association (grant AHA94010440 [A.S.W.]).

Read at the Seventy-eighth Annual Meeting of The American Association for Thoracic Surgery, Boston, Mass, May 3-6, 1998.

Received for publication April 6, 1998. Revisions requested May 27, 1998. Revisions received Sept 21, 1998. Accepted for publication Sept 21, 1998. Address for reprints: Thomas Yeh, Jr, MD, PhD, Division of Cardiovascular Surgery, University of Louisville, 201 Abraham Flexner Way, No 1200, Louisville, KY 40202.

Objectives: The depressed myocardial function observed in brain dead organ donors has been attributed to massive sympathetic discharge and catecholamine cardiotoxicity. Because elevated catecholamines are associated with altered myocardial gene expression, we investigated whether acute brain death from increased intracranial pressure alters the expression of myocardial gene products important in contractility.
Methods: A balloon expansion model was used to increase intracranial pressure in rabbits (n = 22). At timed intervals after brain death, mean arterial pressure, heart rate, electrocardiograms, histologic myocardial injury, and systemic catecholamines were assessed. Messenger RNA levels encoding myofilaments, adrenergic receptors, sarcoplasmic reticulum proteins, transcription factors, and stress-induced programs were measured with blot hybridization of total left ventricular RNA.
Results: Increased intracranial pressure induced an immediate pressor response that temporally coincided with diffuse electrocardiographic ST segment changes. Systemic epinephrine and norepinephrine levels concurrently increased (5- to 8-fold within 1 minute), then fell below baseline within 2 hours, and remained depressed at 4 hours. By 1 hour, histologic injury was evident. Four hours after the induction of increased intracranial pressure, levels of messenger RNA–encoding skeletal and cardiac -actins, egr-1, and heat shock protein 70 were significantly increased. Sham-operated animals did not exhibit these changes.
Conclusions: Select changes in myocardial gene expression occur in response to increased intracranial pressure and implicate ventricular remodeling in the myocardial dysfunction associated with acute brain death.

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