ACCELERATED RECOVERY OF POSTISCHEMIC STUNNED MYOCARDIUM AFTER INDUCEDEXPRESSION OF MYOCARDIAL HEAT-SHOCK PROTEIN (HSP70)

In vitro studies that interventions targeted at myocardial gene regula tion of endogenous cytoprotective elements, such as heat-shock protein , may attenuate myocardial ischemic injury. We tested the hypothesis t hat heat shock-induced expression of myocardial heat-shock protein bef ore ischemia accelerates functional recovery of postischemic stunned m yocardium in the intact circulation. Sixteen dogs underwent partial fe moral arteriovenous bypass and core temperature was raised to 42 degre es C for 15 minutes in eight dogs (heat-shocked) and maintained at 37 degrees C in eight dogs (nonheat-shocked). After 24 hours dogs were st udied to measure myocardial segment length in the circumflex artery re gion with ultrasonic dimension transducers, left ventricular pressure with a micromanometer, and circumflex coronary flow with an ultrasonic probe. Regional contractile function was quantified by the area benea th the linear preload recruitable stroke work relationship at baseline and at intervals during reperfusion after a 15-minute circumflex arte ry occlusion followed by 3 hours of reperfusion. Baseline and peak rep erfusion hyperemic circumflex flows were 37 +/- 9 ml-min and 154 +/- m l/min, respectively, in heat-shocked dogs (p < 0.001) and 46 +/- 24 ml /min and 171 +/- 57 ml/min, respectively, in nonheat-shocked dogs (p < 0.001), with no differences between groups (p = not significant) at a ny time during reperfusion. Heart rate and left ventricular peak press ure, end-diastolic pressure, and first derivative of left ventricular pressure were similar (all p = not significant in heat-shocked and non heat-shocked dogs. Ischemia reduced preload recruitable stroke work re lationship to 32% +/- 8% control (p < 0.001) in heat-shocked dogs and to 19% +/- 15% control in nonheat-shocked dogs (p < 0.001) at 15 minut es of reperfusion, indicating a similar (p = not significant) initial degree of injury. During 3 hours of reperfusion, preload recruitable s troke work relationship returned to 80% +/- 38% control in heat-shocke d dogs but to only 33% +/- 13% control in nonheat-shocked dogs (p < 0. 0001). Myocardial expression of heat-shock protein, quantified by opti cal densitometry of Western blots using an antibody specific for HSP70 , was greater in heat-shocked than in nonheat-shocked dogs (108 +/- 27 versus 71 +/- 14 densitometry units, p < 0.005). Exact causal mechani sms remain to be defined, but these data indicate (1) hyperthermic byp ass triggers induction of myocardial heat-shock protein and (2) elevat ed myocardial heat-shock protein is associated with accelerated recove ry of stunned myocardium. Promotion of endogenous molecular cytoprotec tive systems represents a novel and potentially useful strategy for my ocardial protection.