Published online before print March 4, 2004, doi: 10.1161/01.RES.0000124934.84048.DF
© 2004 American Heart Association, Inc.
Cellular Biology |
Cellular Mechanisms of Contractile Dysfunction in Hibernating Myocardium
From the Laboratories of Experimental Cardiology (V.B., F.R.H., I.D.S., K.R.S.), Cardiac Imaging (F.W., C.D., P.C., B.B., G.R.S.), and Pathology (E.V.), University of Leuven, Leuven, Belgium; Laboratory for Physiology (J.v.d.V., G.J.M.S.), VU University Medical Center, Amsterdam, the Netherlands; Institute of Pathophysiology (F.R.H.), University of Essen, Essen, Germany.
Correspondence to Karin R. Sipido, MD, PhD, Laboratories 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
Ischemic heart disease is a leading cause of chronic heart failure. Hibernation (ie, a chronic reduction of myocardial contractility distal to a severe coronary stenosis and reversible on revascularization) is an important contributing factor. The underlying cellular mechanisms remain however poorly understood. In young pigs (n=13, ISCH), an acquired coronary stenosis >90% (4 to 6 weeks) resulted in the development of hibernating myocardium. Single cardiac myocytes from the ISCH area were compared with cells from the same area obtained from matched normal pigs (n=12, CTRL). Myocytes from ISCH were larger than from CTRL. In field stimulation, unloaded cell shortening was reduced and slower in ISCH; relaxation was not significantly different. The amplitude of the [Ca2+]i transient was not significantly reduced, but reducing [Ca2+]o for CTRL cells could mimic the properties of ISCH, inducing a significant reduction of contraction, but not of [Ca2+]i. Action potentials were longer in ISCH. With square voltage-clamp pulses of equal duration in ISCH and CTRL, the amplitude of the [Ca2+]i transient was significantly smaller in ISCH, as was the Ca2+ current. Near-maximal activation of the myofilaments resulted in smaller contractions of ISCH than of CTRL cells. There was no evidence for increased degradation of Troponin I. In conclusion, cellular remodeling is a major factor in the contractile dysfunction of the hibernating myocardium. Myocytes are hypertrophied, action potentials are prolonged, and L-type Ca2+ currents and Ca2+ release are decreased. The steep [Ca2+]i dependence of contraction and possibly a reduction of maximal myofilament responsiveness further enhance the contractile deficit.
Key Words: ischemia • hibernation • myocytes • ion channels • Ca2+ current
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