Abstract
End-stage heart failure is believed to involve depressed cardiomyocyte
contractility and Ca2+ transients. However, the time course of these
alterations is poorly understood. We examined alterations in myocyte
excitation-contraction coupling in a mouse model of early congestive
heart failure (CHF) following myocardial infarction. One week after
myocardial infarction was induced by ligation of the left coronary
artery, CHF mice were selected based on established criteria (increased
left atrial diameter, increased lung weight). Sham-operated animals
(SHAM) served as controls. Echocardiographic measurements showed
decreased global function in early CHF relative to SHAM, but increased
local function in viable regions of the myocardium which deteriorated
with time. Cardiomyocytes isolated from the non-infarcted septum
also exhibited larger contractions in early CHF than SHAM (CHF=219.6+/-15.3\%
of SHAM values, P<0.05; 1 Hz field stimulation), and relaxation was
more rapid (time to 50\% relaxation=82.9+/-5.5\% of SHAM values,
P<0.05). Ca2+ transients (fluo-4 AM) were larger and decayed more
rapidly in CHF than SHAM during both field stimulation (1 Hz) and
voltage-clamp steps. Sarcoplasmic reticulum (SR) Ca2+ content was
increased. Western blots showed that while SR Ca2+ ATPase (SERCA)
expression was unaltered in CHF, phospholamban (PLB) was downregulated
(60+/-11\% of SHAM values, P<0.05). Thus, an increased SERCA/PLB
ratio in CHF may promote SR Ca2+ re-uptake. Additionally, peak L-type
Ca2+ current and Na+/Ca2+ exchanger expression were increased in
CHF, suggesting increased sarcolemmal Ca2+ flux. Thus, in early CHF,
alterations in Ca2+ homeostasis improve cardiomyocyte contractility
which may compensate for loss of function in the infarction area.
- action
- animals;
- atpases,
- biological;
- c57bl;
- calcium
- calcium,
- calcium-binding
- calcium-transporting
- cardiac,
- channels,
- contraction,
- enzymology/physiology;
- enzymology/physiopathology;
- exchanger,
- factors
- failure,
- female;
- heart
- inbred
- l-type,
- metabolism/physiopathology;
- metabolism;
- mice,
- mice;
- models,
- myocardial
- myocytes,
- patch-clamp
- physiology;
- potentials,
- proteins,
- reticulum
- reticulum,
- sarcoplasmic
- signaling;
- sodium-calcium
- techniques;
- time
- ventricles,
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