MECHANISMS OF CARDIOMYOCYTE DYSFUNCTION IN HEART-FAILURE FOLLOWING MYOCARDIAL-INFARCTION IN RATS

Available information regarding the cellular and molecular mechanisms for reduced myocardial function after myocardial infarction (MI) is sc arce. In rats with congestive heart failure (CHF), we examined cardiom yocytes isolated from the non-infarcted region of the left ventricle 6 weeks after ligation of the left coronary artery. Systolic left-ventr icular pressure was reduced and diastolic pressure was markedly increa sed in the CHF-rats. The cardiomyocytes isolated from the CHF-hearts h ad increased resting length, reduced fractional shortening by 31% and a 34% increase in time to 90% relaxation compared to sham cells (P<0.0 1 for all). Peak L-type calcium currents were not significantly change d, but peak calcium transients measured with fura-2 were reduced by 19 % (P<0.01). Moreover, the decline of the calcium transients as measure d by the time constant of a monoexponential function was significantly increased by 26% (P<0.01). We also examined the contribution of the C a2+-ATPase of the sarcoplasmic reticulum (SR) in the removal of cytoso lic Ca2+ during relaxation by superfusing cells with 1 mu M thapsigarg in that effectively inhibits the Ca2+-ATPase. Relaxation time in CHF-c ells was significantly less prolonged when this drug was used (P<0.01) . This suggests that other mechanisms, probably the Na+-Ca2+ exchanger , contribute significantly to the relaxation rate in CHF, Simultaneous measurements of fura-2 transients and mechanical shortening did not r eveal any alteration in the calcium-myofilament sensitivity in CHF. Ou r study clearly shows reduced shortening and prolonged relaxation in c ardiomyocytes isolated from non-infarcted region of the left ventricle in heart failure. Moreover, we were able to relate the observed cardi omyocyte dysfunction to changes in specific steps in the excitation-co ntraction coupling. (C) 1998 Academic Press