Enhanced Protection of Heat Shock in Myocardial Infarction: Inhibition of Detrimental Effect of Systemic Hyperthermia E.K. Iliodromitis, 1 G.K. Karavolias, 1 E. Bo~lis, 1 , D.M. Yellon, 2 and D.Th. Kremastinos 1 1 Second Department of Cardiology, Onassis Cardiac Surgery Center, Athens, Greece; 2 The Hatter Institute for Cardiovascular Studies, Department of Academic Cardiology, University College London Hospitals, UK Summary. We have shown that isolated blood-perfused heat-stressed hearts are protected only when the blood donor animal has not been exposed to hyperthermia. Sys- tematic hyperthermia results in larger infarction of both isolated control and heat-stressed hearts. In this study we investigated whether indomethacin inhibits in vivo the det- rimental effect of hyperthermia. Male rabbits were divided into four groups, that is A(30), B(30), C(30), and D(30), representing hearts that ultimately received 30 minutes of ischemia. In a second series, rabbits were divided into groups A(45), B(45), (C45), and D(45) representing hearts that ultimately received 45 minutes of ischemia, and in a third series were divided into groups A(HSP), B(HSP), C(HSP), and D(HSP) representing animals that were heat shocked and their hearts were used to measure heat shock proteins. All the A groups (heat shocked) were subjected to 42°C hyperthermia, all the B groups to the same procedure but with the addition of indomethacin (heat shocked + indomethacin), all the C groups served as controls, and all the D groups were treated with indomethacin only (control + indomethacin). Twenty-four hours later, all (30) and (45) groups were subjected to ischemia, whereas hearts from all (HSP) groups were harvested for heat shock protein meas- urements. When the animals were exposed to 30-minute ischemia, a signi~cant difference in the infarcted to risk zone ratio (%I/R) was observed: A(30): 33.0  5.2, B(30): 16.1  4.4 [conferring a 51.2% reduction in infarct size, P  0.05], C(30): 48.9  4.0, and D(30): 47.8  3.8 [P  0.001 vs. B (30) and P  0.05 vs. A(30)]. However, the %I/R did not differ among any of the (45) groups. Heat shock pro- teins themselves were seen to increase in A(HSP) and B(HSP) groups. Indomethacin enhances the bene~cial ef- fect of heat shock after 30-minute ischemia in vivo, reducing the infarct size by 51.2% in comparison with heat shock. Cardiovasc Drugs Ther 1999:13 Key Words. heat shock proteins, myocardial infarction, pro- tection, indomethacin, in vivo rabbits Heat shock proteins are synthesized in the heart and other tissues of various species that have been pre- viously exposed to hyperthermia. Among the ~ve ma- jor groups of heat shock proteins, the 70-kDa family has been associated with improved postischemic ven- tricular recovery of function and preservation of devel- oped pressure [1,2]. Heat stress seems to protect in vivo against myocardial infarction for a certain period of time [3,4], but this protection is blunted when the ischemia becomes more sustained [5]. Similarly, we have shown that heat-stressed hearts are protected against infarction, in a model of isolated blood perfused hearts, but this protection disappears when the sup- port animal (blood donor) is previously exposed to hy- perthermia [6]. Because the whole body increase in temperature appears to induce the in_ammatory re- sponse [7–9], it is reasonable to assume that blood- borne in_ammatory agents are responsible for par- tially reversing the protective effect that the heat shock confers in vitro. Therefore, the aim of the pre- sent study was to investigate whether the detrimental effect of in_ammation could be inhibited by an an- tiin_ammatory agent in an in situ heart. Indomethacin was selected as a conventional nonsteroidal antiin_am- matory drug. Methods Animals New Zealand White male rabbits weighing 2.5–3.1 kg were divided into two main groups, series 30 (destined to be subjected to 30-minute ischemia) and series 45 (destined to be subjected to 45-minute ischemia). Each series consisted of four groups (A, B, C, and D, respec- tively) which were characterized with the number 30 or 45, depending on the series to which they belong. A third series of experiments, called series HSP, also con- sisting of four groups, was used for the measurement Address for correspondence: Efstathios K. Iliodromitis, MD, Onassis Cardiac Surgery Center, 356 Sygrou Ave., 17674 Athens, Greece E-mail: elbee@ath.forthnet.gr Received 28 September 1998; receipt/review 2 months; accepted in revised form 14 December 1998 223 Cardiovascular Drugs and Therapy 1999:13:223–231 © Kluwer Academic Publishers. Boston. Printed in U.S.A.