Cellular Mechanisms of Contractile Dysfunction in Hibernating Myocardium

• Published in: Circulation research 2004-04, Vol.94 (6), p.794-801
• Main Authors: Bito, Virginie, Heinzel, Frank R, Weidemann, Frank, Dommke, Christophe, van der Velden, Jolanda, Verbeken, Erik, Claus, Piet, Bijnens, Bart, De Scheerder, Ivan, Stienen, Ger J.M, Sutherland, George R, Sipido, Karin R
• Format: Article
• Language: English
• Subjects: Actin Cytoskeleton - physiology; Action Potentials; Animals; Biological and medical sciences; Calcium Channels, L-Type - drug effects; Calcium Channels, L-Type - metabolism; Calcium Signaling; Cell Size; Coronary Stenosis - complications; Fundamental and applied biological sciences. Psychology; Hypertrophy; Ion Transport - drug effects; Myocardial Contraction; Myocardial Stunning - etiology; Myocardial Stunning - physiopathology; Myocardium - pathology; Myocytes, Cardiac - pathology; Myocytes, Cardiac - physiology; Nifedipine - pharmacology; Patch-Clamp Techniques; Swine; Troponin I - metabolism; Vertebrates: cardiovascular system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000124934.84048.DF

ABSTRACT—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 [Ca]i transient was not significantly reduced, but reducing [Ca]o for CTRL cells could mimic the properties of ISCH, inducing a significant reduction of contraction, but not of [Ca]i. Action potentials were longer in ISCH. With square voltage-clamp pulses of equal duration in ISCH and CTRL, the amplitude of the [Ca]i transient was significantly smaller in ISCH, as was the Ca 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 Ca currents and Ca release are decreased. The steep [Ca]i dependence of contraction and possibly a reduction of maximal myofilament responsiveness further enhance the contractile deficit.