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CARDIOVASCULAR |
1 Institute for Experimental Medical Research, Ullevaal University Hospital, Oslo, Norway
2 Center for Heart Failure Research, University of Oslo, Oslo, Norway
3 Department of Cardiology, Ullevaal University Hospital, Oslo, Norway
4 Department of Biostatistics, Rikshospitalet, Oslo, Norway
In cardiac myocytes, initiation of excitation–contraction coupling is highly localized near the T-tubule network. Myocytes with a dense T-tubule network exhibit rapid and homogeneous sarcoplasmic reticulum (SR) Ca2+ release throughout the cell. We examined whether progressive changes in T-tubule organization and Ca2+ release synchrony occur in a murine model of congestive heart failure (CHF). Myocardial infarction (MI) was induced by ligation of the left coronary artery, and CHF was diagnosed by echocardiography (left atrial diameter >2.0 mm). CHF mice were killed at 1 or 3 weeks following MI (1-week CHF, 3-week CHF) and cardiomyocytes were isolated from viable regions of the septum, excluding the MI border zone. Septal myocytes from SHAM-operated mice served as controls. T-tubules were visualized by confocal microscopy in cells stained with di-8-ANEPPS. SHAM cells exhibited a regular striated T-tubule pattern. However, 1-week CHF cells showed slightly disorganized T-tubule structure, and more profound disorganization occurred in 3-week CHF with irregular gaps between adjacent T-tubules. Line-scan images of Ca2+ transients (fluo-4 AM, 1 Hz) showed that regions of delayed Ca2+ release occurred at these gaps. Three-week CHF cells exhibited an increased number of delayed release regions, and increased overall dyssynchrony of Ca2+ release. A common pattern of Ca2+ release in 3-week CHF was maintained between consecutive transients, and was not altered by forskolin application. Thus, progressive T-tubule disorganization during CHF promotes dyssynchrony of SR Ca2+ release which may contribute to the slowing of SR Ca2+ release in this condition.
(Received 10 February 2006;
accepted after revision 11 May 2006;
first published online 18 May 2006)
Corresponding author W. E. Louch: Institute for Experimental Medical Research, 4. etg. Kirurgisk Bygning, Ullevaal University Hospital, 0407 Oslo, Norway. Email: w.e.louch{at}medisin.uio.no
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