Journal of Electrocardiology Vol. 31 Supplement Cellular Mechanisms for the Slow Phase of the Frank-Starling Response Wolfgang F. Bluhm, PhD,* Derrick Sung, MS,~- Wilbur Y. W. Lew, MD,*$ Alan Garfinkel, PhD,§ and Andrew D. McCulloch, PhD~- Abstract: Following a step increase in sarcomere length, isometric cardiac muscle tension increases instantaneously by the Frank-Staffing mechanism. In isolated papillary muscle and myocytes, there is an additional significant rise in developed tension over the following 15 min due to an unknown mechanism. This slow change in tension could not be explained by mechanical heterogeneity of the muscle preparations or by an increase in myofilament sensitivity to Ca2+. The slow change in tension was not dependent on sarcoplasmic reticulum Ca2+ loading assessed with rapid cooling contractures, and was not significantly altered by sarcoplasmic reticulum Ca2+ depletion (ryanodine) or inhibition of sarcoplas- mic reticulum Ca2+ reuptake (cydopiazonic acid). We used the Luo-Rudy ionic model of the ventricular myocyte together with a model of the length-dependent myofilament activation by Cax+ to examine the effects of step changes in the parameters of sarcolemmal ion fluxes as possible mechanisms for the slow change in stress. The slow increase in tension was simulated by step changes in the Na+-K + pump or Na + leak currents, suggesting that the slow change in stress may be caused by length induced changes in Na + fluxes. The model also predicted a slow increase in the magnitude of the initial repolarization during phase 1 of the action potential. The combination of experimental and computational models used in this investigation represents a valuable technique in eluddating the cellular mechanisms of fundamental processes in cardiac exaltation-contraction coupling. Key words: heart, Frank-Starling mechanism, excitation-contraction cou- pling, Luo-Rudy model. Active stress in cardiac muscle increases with mus- de length. This fundamental principle has been From the *Department of Medicine, University of California, San Diego, California; t-Department of Bioengineering, University of Cali- fornia, San Diego, California; ¢Cardiology Division, Department of Veterans Affairs Medical Center, San Diego, California; and ~Depart- ments of Physiological Science and Medicine (Cardiology), University of California, Los Angeles, California. Supported by NIH grant I-IL-41603, NSF grant BES-9634974, the Department of Veterans Affairs, and the American Heart Association. Reprint requests: Andrew D. McCulloch, PhD, Department of Bioengineering, Institute for Biomedical Engineering, 9500 Gil- man Drive, University of California, San Diego, La Jolla, CA 92093-0412. Copyright © 1998 by Churchill Livingstone ® 0022-0736/98/310S-100355.00/0 known since the classic studies of Frank and Starling almost a century ago. Over the last two decades, it has become evident that this increase is primarily caused by length-dependent activation of the thin filament. The length-tension relationship has long been consid- ered a fundamental property of isolated cardiac mus- cle preparations and has been the subject of numer- ous review articles (i-5). However, the contractile force of cardiac musde does not depend on the instantaneous muscle length alone. Active and pas- sive forces in cardiac muscle both depend on the time history of sarcomere length. In 1973, Parmley and Chuck (6) first showed that the immediate increase in cardiac muscle tension 13