title: Mechanisms of cardiomyocyte dysfunction in heart failure following myocardial infarction in rats.
abstract: 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 microM 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.
authors.affiliation: Institute for Experimental Medical Research, University of Oslo, Oslo, N-0407, Norway.
authors.forename: E
authors.initials: E
authors.lastname: Holt
authors.forename: T
authors.initials: T
authors.lastname: Tønnessen
authors.forename: P K
authors.initials: PK
authors.lastname: Lunde
authors.forename: S O
authors.initials: SO
authors.lastname: Semb
authors.forename: J A
authors.initials: JA
authors.lastname: Wasserstrom
authors.forename: O M
authors.initials: OM
authors.lastname: Sejersted
authors.forename: G
authors.initials: G
authors.lastname: Christensen
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D016257:Fura-2; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology*; D006352:Heart Ventricles / Q000473:pathology; D006439:Hemodynamics; D008297:Male; D009119:Muscle Contraction; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology*; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: D015220:Calcium Channels; D005576:Colforsin; D019284:Thapsigargin; D012964:Sodium; D000252:Calcium-Transporting ATPases; D002118:Calcium; D016257:Fura-2