Heart failure after myocardial infarction: altered excitation-contraction coupling.
BACKGROUND
Heart failure (HF) frequently follows the occurrence of myocardial infarction (MI). Questions about how HF develops and what cellular defects contribute to this dysfunction led to this study. Methods and Results-- MI was induced in rats by coronary artery ligation. Clinical examination of the post-MI (PMI) surviving animals indicated that they were in overt HF by all measures. Cellular examination of the cardiomyocytes by patch-clamp and confocal [Ca(2+)](i) imaging methods indicated that cellular function was significantly compromised. At the single-cell level, [Ca(2+)](i) transient amplitudes were reduced and contractions were decreased and slowed, although Ca(2+) current (I(Ca)) remained unchanged. The excitation-contraction coupling (ECC) gain function measured as Delta[Ca(2+)](i)/I(Ca) was significantly decreased. Ouabain, a cardiotonic steroid that blocks the Na(+),K(+)-ATPase and activates Ca(2+) entry via cardiac Na(+) channels, largely alleviated this defect.


CONCLUSIONS
After MI, I(Ca) becomes less able to trigger release of Ca(2+) from the sarcoplasmic reticulum. This failure of ECC is a major factor contributing to the development of contractile dysfunction and HF in PMI animals. The improved ECC gain, enhanced Ca(2+) entry, and augmented Ca(2+) signaling due to cardiotonic steroids contribute to the beneficial effects of these agents.
Gómez
A M
AM
INSERM-U.390, IFR-3, Montpellier, France. agomez@montp.inserm.fr
Guatimosim
S
S
Dilly
K W
KW
Vassort
G
G
Lederer
W J
WJ
D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology; D048429:Cell Size / Q000187:drug effects; D006333:Heart Failure / Q000209:etiology / Q000503:physiopathology*; D006984:Hypertrophy; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D009200:Myocardial Contraction / Q000502:physiology; D009203:Myocardial Infarction / Q000150:complications* / Q000401:mortality / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010042:Ouabain / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D015996:Survival Rate; D013779:Tetrodotoxin / Q000494:pharmacology
D015220:Calcium Channels; D002316:Cardiotonic Agents; D013779:Tetrodotoxin; D010042:Ouabain; D002118:Calcium