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Mechanisms of cardiomyocyte dysfunction in heart failure following myocardial infarction in rats
E Holt1, T Tønnessen, P K Lunde
1Institute for Experimental Medical Research, University of Oslo, Oslo, N-0407, Norway.
Insights
Cardiomyocyte dysfunction, including reduced shortening and prolonged relaxation, occurs in heart failure after myocardial infarction. This study investigates the cellular mechanisms behind impaired cardiac function in non-infarcted heart regions.
Area of Science:
- Cardiovascular Biology
- Cardiac Physiology
- Molecular Cardiology
Background:
- Information on cellular and molecular mechanisms of reduced myocardial function post-myocardial infarction (MI) is limited.
- Heart failure (HF) following MI leads to significant changes in cardiac structure and function.
Purpose of the Study:
- To investigate the cellular and molecular mechanisms underlying reduced myocardial function in cardiomyocytes from the non-infarcted region of the left ventricle in a rat model of congestive heart failure (CHF).
- To elucidate the alterations in excitation-contraction coupling contributing to cardiac dysfunction in CHF.
Main Methods:
- Isolated cardiomyocytes from sham and CHF rats (6 weeks post-MI) were studied.
- Measurements included cell mechanics (shortening, relaxation), L-type calcium currents, and intracellular calcium transients (fura-2).
- The role of sarcoplasmic reticulum Ca2+-ATPase was assessed using thapsigargin.
Main Results:
- CHF cardiomyocytes exhibited increased resting length, reduced fractional shortening (31%), and prolonged relaxation (34%).
- Peak calcium transients were reduced (19%), and their decline was slower, indicating impaired calcium handling.
- Inhibition of Ca2+-ATPase partially restored relaxation, suggesting increased reliance on the Na+-Ca2+ exchanger.
Conclusions:
- Cardiomyocytes from the non-infarcted region of failing hearts show significant contractile dysfunction and impaired relaxation.
- Alterations in excitation-contraction coupling, particularly in calcium handling and removal, contribute to cardiomyocyte dysfunction in heart failure.
- The Na+-Ca2+ exchanger plays a more prominent role in calcium removal during relaxation in CHF hearts.
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.