Almost 26% of patients may develop limited left ventricular dilatation within 4 weeks after first infarction, which helps to restore cardiac index and stroke index at rest and to preserve exercise performance and therefore remains compensatory. A somewhat smaller group (20%) develops progressive structural left ventricular dilatation, which is compensatory at first, then progresses to noncompensatory dilatation, and finally results in severe global left ventricular dysfunction. In these patients, depression of global ejection fraction probably results from impairment of function of initially normally contracting myocardium. Early predictors from multivariate analysis allow identification of patients at high risk for progressive left ventricular dilatation and chronic ventricular dysfunction within 4 weeks after acute infarction.

IntroductionThe purpose of this study was to test the hypothesis that energy metabolism is impaired in residual intact myocardium of chronically infarcted rat heart, contributing to contractile dysfunction. Myocardial infarction (MI) was induced in rats by coronary artery ligation. (6), aortic stenosis (7), dilated cardiomyopathy in the Syrian hamster (8), uninephrectomy plus steroid treatment (9), or the spontaneously hypertensive rat (10). The purpose of the present work was, therefore, to define performance, oxygen consumption, and parameters of energy reserve, i.e., tissue contents of ATP and creatine phosphate (CP), creatine kinase (CK) activity and isoenzyme distribution, and phosphoryl transfer rates via CK (using 3P-magnetization transfer), in normal rat heart and in residual intact myocardium after MI. Using these measurements, we directly tested whether changes in energy metabolism can contribute to contractile dysfunction in post-MI heart. MethodsAnimals and experimental MI. Infarcts or sham operations were carried out in 12-wk-old Wistar rats, kept in a 12-h light-dark cycle. Left anterior descending coronary artery (LAD) ligation was performed by a previously described technique (1, 11). Briefly, a left thoracotomy was performed under ether anesthesia and positive pressure ventilation. The heart was rapidly exteriorized by applying gentle pressure on both sides of the thorax. The LAD was ligated between the pulmonary outflow tract and the left atrium. The heart was then replaced into the thorax, lungs were inflated by increasing positive end-expiratory pressure, and the wound was closed immediately. Sham operation was performed using an identical procedure except that the suture was passed under the coronary artery without ligation. Mortality rate of infarcted rats for the first 24 h after the operation was 40-50%. Surviving rats were kept on commercial rat chow and water ad libitum. All procedures conformed to the guiding principles of the American Physiological Society. Isolated rat heart preparation. 8 wk after LAD ligation or sham operation, rats were anesthetized by injecting 20 mg pentobarbital sodium intraperitoneally. After thoracotomy, the heart was rapidly excised and immersed in ice-cold buffer. The aorta was dissected free and mounted onto a cannula attached to a perfusion apparatus, as described previously (12). Retrograde perfusion of the heart was started in the 1092Neubauer et al.J. Clin. Invest.C) The

Abstract-The plasma membrane calmodulin-dependent calcium ATPase (PMCA) is a calcium-extruding enzyme controlling Ca 2ϩ homeostasis in nonexcitable cells. However, its function in the myocardium is unclear because of the presence of the Na ϩ /Ca 2ϩ exchanger. We approached the question of the physiological function of the calcium pump using a transgenic "gain of function" model. Transgenic rat lines carrying the human PMCA 4 cDNA under control of the ventricle-specific myosin light chain-2 promoter were established, and expression in the myocardium was ascertained at the mRNA, protein, and functional levels. In vivo hemodynamic measurements in adult homozygous animals showed no differences in baseline and increased cardiac performance recruited by volume overload compared with controls. No differences between transgenic and control cardiomyocytes were found in patch clamp voltage dependence, activation/inactivation behavior of the L-type Ca 2ϩ current, or fast [Ca 2ϩ ] i transients (assessed by the Fura-2 method). To test whether the PMCA might be involved in processes other than beat-to-beat regulation of contraction/relaxation, we compared growth processes of neonatal transgenic and control cardiomyocytes. A 1.6-and 2.3-fold higher synthesis rate of total protein was seen in cells from transgenic animals compared with controls on incubation with 2% FCS for 24 hours and 36 hours, respectively. An effect of similar magnitude was observed using 20 mol/L phenylephrine. A 1.4-fold-and 2.0-fold-higher protein synthesis peak was seen in PMCA-overexpressing cardiomyocytes after stimulation with isoproterenol for 12 hours and 24 hours, respectively. Because pivotal parts of the ␣-and ␤-adrenergic signal transduction pathways recently have been localized to caveolae, we tested the hypothesis that the PMCA might alter the amplitude of ␣-and ␤-adrenergic growth signals by virtue of its localization in caveolae. Biochemical as well as immunocytochemical studies suggested that the PMCA in large part was colocalized with caveolin 3 in caveolae of cardiomyocytes. These results indicate that the sarcolemmal Ca 2ϩ -pump has little relevance for beat-to-beat regulation of contraction/relaxation in adult animals but likely plays a role in regulating myocardial growth, possibly through modulation of caveolar signal transduction. (Circ Res. 1998;83:877-888.)