Cellular mechanisms of contractile dysfunction in hibernating myocardium.
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.
Laboratories of Experimental Cardiology, University of Leuven, Leuven, Belgium.
Virginie
V
Bito
Frank R
FR
Heinzel
Frank
F
Weidemann
Christophe
C
Dommke
Jolanda
J
van der Velden
Erik
E
Verbeken
Piet
P
Claus
Bart
B
Bijnens
Ivan
I
De Scheerder
Ger J M
GJ
Stienen
George R
GR
Sutherland
Karin R
KR
Sipido
D008841:Actin Cytoskeleton / Q000502:physiology; D000200:Action Potentials; D000818:Animals; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling; D048429:Cell Size; D023921:Coronary Stenosis / Q000150:complications; D006984:Hypertrophy; D017136:Ion Transport / Q000187:drug effects; D009200:Myocardial Contraction; D017682:Myocardial Stunning / Q000209:etiology / Q000503:physiopathology*; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000473:pathology* / Q000502:physiology; D009543:Nifedipine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D013552:Swine; D019210:Troponin I / Q000378:metabolism
D020746:Calcium Channels, L-Type; D019210:Troponin I; D009543:Nifedipine