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(Circulation Research. 2008;102:338.)
© 2008 American Heart Association, Inc.

Cellular Biology

Remodeling of T-Tubules and Reduced Synchrony of Ca²⁺ Release in Myocytes From Chronically Ischemic Myocardium

Frank R. Heinzel, Virginie Bito, Liesbeth Biesmans, Ming Wu, Elke Detre, Frederik von Wegner, Piet Claus, Steven Dymarkowski, Frederik Maes, Jan Bogaert, Frank Rademakers, Jan D’hooge, Karin Sipido

From the Division of Experimental Cardiology (F.R.H., V.B., L.B., E.D., K.S.), Division of Cardiac Imaging (M.W., P.C., F.R., J.D’h.), Division of Radiology (S.D., J.B.), Department of Electrical Engineering (F.M.), University Hospital Gasthuisberg and University of Leuven, Belgium; and Medical Biophysics (F.v.W.), Institute for Physiology and Pathophysiology, University of Heidelberg, Germany. F.R.H. is currently at the Division of Cardiology, Medical University of Graz, Austria.

Correspondence to Karin R. Sipido, MD, PhD, Laboratory of Experimental Cardiology, KUL, Campus Gasthuisberg O/N 7th Floor, Herestraat 49, B-3000 Leuven, Belgium. E-mail Karin.Sipido{at}med.kuleuven.ac.be

In ventricular cardiac myocytes, T-tubule density is an important determinant of the synchrony of sarcoplasmic reticulum (SR) Ca²⁺ release and could be involved in the reduced SR Ca²⁺ release in ischemic cardiomyopathy. We therefore investigated T-tubule density and properties of SR Ca²⁺ release in pigs, 6 weeks after inducing severe stenosis of the circumflex coronary artery (91±3%, N=13) with myocardial infarction (8.8±2.0% of total left ventricular mass). Severe dysfunction in the infarct and adjacent myocardium was documented by magnetic resonance and Doppler myocardial velocity imaging. Myocytes isolated from the adjacent myocardium were compared with myocytes from the same region in weight-matched control pigs. T-tubule density quantified from the di-8-ANEPPS (di-8-butyl-amino-naphthyl-ethylene-pyridinium-propyl-sulfonate) sarcolemmal staining was decreased by 27±7% (P<0.05). Synchrony of SR Ca²⁺ release (confocal line scan images during whole-cell voltage clamp) was reduced in myocardium myocytes. Delayed release (ie, half-maximal [Ca²⁺]_i occurring later than 20 ms) occurred at 35.5±6.4% of the scan line in myocardial infarction versus 22.7±2.5% in control pigs (P<0.05), prolonging the time to peak of the line-averaged [Ca²⁺]_i transient (121±9 versus 102±5 ms in control pigs, P<0.05). Delayed release colocalized with regions of T-tubule rarefaction and could not be suppressed by activation of protein kinase A. The whole-cell averaged [Ca²⁺]_i transient amplitude was reduced, whereas L-type Ca²⁺ current density was unchanged and SR content was increased, indicating a reduction in the gain of Ca²⁺-induced Ca²⁺ release. In conclusion, reduced T-tubule density during ischemic remodeling is associated with reduced synchrony of Ca²⁺ release and reduced efficiency of coupling Ca²⁺ influx to Ca²⁺ release.

Key Words: myocardial infarction • contractility • myocytes • calcium

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