Cardiac Effects of Thalidomide 29 Cardiovascular Toxicology Humana Press Volume 4, 2004 29 *Author to whom all correspondence and reprint requests should be addresse: Robert L. Hamlin, 6456 Fiesta Drive, Columbus, OH 43235. E-mail: rhamlin @qtestlabs.com. Robert L. Hamlin is an unpaid consultant to QTest laboratories, Inc. Received: 8/11/03 Revised: 10/20/03 Accepted: 11/5/03 Cardiovascular Toxicology, vol. 4, no. 1, 29–36, 2004 Effects of Thalidomide on QTc, Inotropy, and Lusitropy in the Isolated Guinea Pig Heart Robert L. Hamlin, 1, * Anusak Kijtawornrat, 1 Bruce W. Keene, 2 Tomohiro Nakayama, 1 Hitomi Nakayama, 1 David M. Hamlin, 3 and Tammy A. Arnold 3 1 Department of Veterinary Biosciences, The Ohio State University, Columbus, OH; 2 Department of Veterinary Clinical Sciences, North Carolina State University, Raleigh, NC; and 3 QTest Laboratories, Inc., Columbus, OH Cardiovascular Toxicology (2004) 04 29–36 $25.00 (http://www.cardiotox.com) © Copyright 2004 by Humana Press Inc. All rights of any nature whatsoever reserved. 1530-7905/01 Humana Press Abstract There has been a resurgence in the use of thalidomide over the past several years; however, little is known about its potential cardiac toxicity. Isolated, perfused guinea pig hearts were exposed to escalating concentrations of thalidomide or vehicle, and changes in RR interval, QT duration and QTc duration, and left ventricular inotropy and lusitropy comparing escalating concentrations of thalidomide with vehicle were sought. RR interval length- ened and QTc prolonged significantly at 10 μM concentrations. QT did not change. dP/dt max increased and dP/dt min decreased in response to thalido- mide. Based on results using this preparation, thalidomide has a potential liability for lengthening QTc, but only at concentrations of 10 μM or greater. It possesses both positive inotropic and positive lusitropic properties. Key Words: Thalidomide; cardiac toxicity; QTc; torsadogenicity; inotropy; lusitropy. Introduction Thalidomide (C 13 H 10 N 2 O 4 , MW 258.2) is a glutamic acid derivative composed of a two-ringed structure with an asymmetric carbon in the glutarimide ring. Before 1962 it was used to prevent nausea in pregnant woman. However, after thalidomide was demonstrated to be teratogenic (1–3), its use was virtually extinguished. Since then, there has been a resurgence (4,5) in its use for the acute management of various conditions, including the cutaneous manifestations of moderate to severe erythema nodosum leprosum through anti-inflammatory/immunomodulatory mechanisms (6,7), graft-vs-host disease (8), multiple myeloma (9), HIV (10), dis- eases that depend on angiogenesis (11), and advanced congestive heart failure (12). We are aware of no studies describing potential cardiac toxicity, and in particular none to identify a potential for retarding ventricular repolarization indicating a liability for producing torsade de pointes. Because thalidomide counteracts the activity of tumor necrosis factor- (12), it is under investigation to explore the