(Circulation. 1999;99:1077-1083.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Origin of Contractile Dysfunction in Heart Failure
Calcium Cycling Versus Myofilaments
From the Section of Molecular and Cellular Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Md (N.G.P., K.H., E.M.), and the Departments of Food Science and Technology (S.M.) and Medical Biochemistry (R.A.A.), Ohio State University, Columbus. Dr Pérez is now at the Center for Cardiovascular Investigation, University of La Plata, Buenos Aires, Argentina.
Correspondence to Eduardo Marbán, MD, PhD, Room 844, Ross Building, Johns Hopkins University School of Medicine, 720 Rutland Ave, Baltimore, MD 21205. E-mail marban{at}welchlink.welch.jhu.edu
Background—Chronic congestive heart failure is a common, often lethal disorder of cardiac contractility. The fundamental pathophysiology of the contractile failure remains unclear, the focus being on abnormal Ca2+ cycling despite emerging evidence for depressed myofilament function.
Methods and Results—We measured intracellular Ca2+ concentration ([Ca2+]i) and contractile force in intact ventricular muscle from SHHF rats with spontaneous heart failure and from age-matched controls. At physiological concentrations of extracellular Ca2+ ([Ca2+]o), [Ca2+]i transients were equal in amplitude in the 2 groups, but [Ca2+]i peaked later in SHHF muscles. Twitch force peaked slowly and was equivalent or modestly decreased in amplitude relative to controls. Steady-state analysis revealed a much greater (53%) depression of maximal Ca2+-activated force in SHHF muscles, which, had other factors been equal, would have produced an equivalent suppression of twitch force. Phase-plane analysis reveals that the slowing of Ca2+ cycling prolongs the time available for Ca2+ to activate the myofilaments in failing muscle, partially compensating for the marked dysfunction of the contractile machinery.
Conclusions—Our results indicate that myofilament activation is severely blunted in heart failure, but concomitant changes in [Ca2+]i kinetics minimize the contractile depression. These results challenge prevailing concepts regarding the pathophysiology of heart failure: the myofilaments emerge as central players, whereas changes in Ca2+ cycling are reinterpreted as compensatory rather than causative.
Key Words: calcium • contractility • heart failure • myocardium
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