Cardiomyocytes hypertrophic status after myocardial infarction determines distinct types of arrhythmia: role of the ryanodine receptor.
The mechanisms responsible for sudden cardiac death in heart failure (HF) are unclear. We investigated early and delayed afterdepolarizations (EADs, DADs) in HF. Cardiomyocytes were enzymatically isolated from the right ventricle (RV) and the septum of rats 8 weeks after myocardial infarction (MI) and sham-operated animals. Membrane capacitance, action potentials (AP) and ionic currents were measured by whole-cell patch-clamp. The [Ca(2+)](i) transients and Ca(2+) sparks were recorded with Fluo-4 during fluorescence measurements. Arrhythmia was triggered in 40% of MI cells (not in sham) using trains of 5 stimulations at 2.0 Hz. EADs and DADs occurred in distinct cell populations both in the RV and the septum. EADs occurred in normal-sized PMI cells (<230 pF), whereas DADs occurred in hypertrophic PMI cells (>230 pF). All cells exhibited prolonged APs due to reduced I(to) current. However, additional modifications in Ca(2+)-dependent ionic currents occurred in hypertrophic cells: a decrease in the inward rectifier K(+) current I(K1), and a slowing of L-type Ca(2+) current inactivation which was responsible for the lack of adaptation of APs to abrupt changes in the pacing rate. The occurrence of spontaneous Ca(2+) sparks, reflecting ryanodine receptor (RyR2) diastolic activity, increased with hypertrophy. The [Ca(2+)](i) transient amplitude, sarcoplasmic reticulum (SR) Ca(2+) load and Ca(2+) sparks amplitude were all inversely correlated with cell size. We conclude that the trophic status of cardiomyocytes determines the type of cellular arrhythmia in MI rats, based on differential electrophysiological remodeling which may reflect early-mild and late-severe or differential modifications in the RyR2 function.
Fauconnier
Jérémy
J
INSERM U637, Université Montpellier1, Department of Cardiovascular Physiopathology, 371 avenue du Doyen Gaston Giraud, F34295 Montpellier Cedex 5, France.
Pasquié
Jean-Luc
JL
Bideaux
Patrice
P
Lacampagne
Alain
A
Richard
Sylvain
S
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism / Q000503:physiopathology*; D016757:Death, Sudden, Cardiac / Q000209:etiology; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D009203:Myocardial Infarction / Q000378:metabolism / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*
D019837:Ryanodine Receptor Calcium Release Channel