Mechanisms of cardiomyocyte dysfunction in heart failure following myocardial infarction in rats

被引:45
|
作者
Holt, E [1 ]
Tonnessen, T
Lunde, PK
Semb, SO
Wasserstrom, JA
Sejersted, OM
Christensen, G
机构
[1] Ulleval Hosp, Expt Med Res Inst, N-0407 Oslo, Norway
[2] Northwestern Univ, Sch Med, Dept Med Cardiol, Chicago, IL USA
[3] Univ Calif San Diego, Dept Med, Mol Cardiol Program, San Diego, CA 92103 USA
关键词
heart failure; myocytes; calcium; sarcoplasmic reticulum;
D O I
10.1006/jmcc.1998.0724
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Available information regarding the cellular and molecular mechanisms for reduced myocardial function after myocardial infarction (MI) is scarce. In rats with congestive heart failure (CHF), we examined cardiomyocytes isolated from the non-infarcted region of the left ventricle 6 weeks after ligation of the left coronary artery. Systolic left-ventricular pressure was reduced and diastolic pressure was markedly increased in the CHF-rats. The cardiomyocytes isolated from the CHF-hearts had increased resting length, reduced fractional shortening by 31% and a 34% increase in time to 90% relaxation compared to sham cells (P<0.01 for all). Peak L-type calcium currents were not significantly changed, but peak calcium transients measured with fura-2 were reduced by 19% (P<0.01). Moreover, the decline of the calcium transients as measured by the time constant of a monoexponential function was significantly increased by 26% (P<0.01). We also examined the contribution of the Ca2+-ATPase of the sarcoplasmic reticulum (SR) in the removal of cytosolic Ca2+ during relaxation by superfusing cells with 1 mu M thapsigargin that effectively inhibits the Ca2+-ATPase. Relaxation time in CHF-cells 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 reveal any alteration in the calcium-myofilament sensitivity in CHF. Our study clearly shows reduced shortening and prolonged relaxation in cardiomyocytes isolated from non-infarcted region of the left ventricle in heart failure. Moreover, we were able to relate the observed cardiomyocyte dysfunction to changes in specific steps in the excitation-contraction coupling. (C) 1998 Academic Press
引用
收藏
页码:1581 / 1593
页数:13
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