Mechanical regulation of cardiac muscle by coupling calcium kinetics with cross-bridge cycling: a dynamic model

Abstract

This study describes the regulation of mechanical activity in the intact cardiac muscle, the effects of the free calcium transients and the mechanical constraints, and emphasizes the central role of the troponin complex in regulating muscle activity. A "loose coupling" between calcium binding to troponin and cross-bridge cycling is stipulated, allowing the existence of cross bridges in the strong conformation without having bound calcium on the neighboring troponin. The model includes two feedback mechanisms: 1) a positive feedback, or cooperativity, in which the cycling cross bridges affect the affinity of troponin for calcium, and 2) a negative mechanical feedback, where the filament-sliding velocity affects cross-bridge cycling. The model simulates the reported experimental force-length and force-velocity relationships at different levels of activation. The dependence of the shortening velocity on calcium concentration, sarcomere length, internal load, and rate of cross-bridge cycling is described analytically in agreement with reported data. Furthermore, the model provides an analytic solution for Hill's equation of the force-velocity relationship and for the phenomena of unloaded shortening velocity and force deficit. The model-calculated changes in free calcium in various mechanical conditions are in good agreement with the available experimental results.

Heterogeneities in myocardial flow and metabolism: exacerbation with abnormal excitation

“…Such studies are needed to provide direct experimental links between local oxygen consumption, local flow, local activation, and local myocardial mechanics, and to provide a practical test of the energetic inferences of the cross-bridge theory of Landesberg and Sideman. 44,45 Theory and experiment go hand in hand; the more complex the known system becomes, the more need there is for a comprehensive model of the system for use in experiment design and interpretation. The modeling and experimental studies discussed here form a small part of a grander effort-the Cardiome Project-just now in its nascent stage.…”

“…This has been explored by Allen and Kurihara 42 and by Allen and Kentish 43 and pulled together in a quantitative comprehensive theoretical study by Landesberg and Sideman. 44,45 It causes reduction in the amount of calcium bound to the myosin ATPase in the "strong" form, implying that the rapid shortening against low resistance decreases ATP hydrolysis. This is termed "shortening deactivation."…”

The mechanical and metabolic basis of myocardial blood flow heterogeneity

“…Gonzalez and Bassingthwaighte (42) obtained ISF volumes of 0.21 ± 0.03 ml/g (SD, N = 432) in intact rabbits by the equilibration with blood of 14 C-sucrose and 58 CoEDTA, trustworthy indicators of ECF space. The estimates obtained in isolated blood-perfused dog hearts by Guller et al (45) were closer to 0.3 ml/g for the extravascular sodium space, but this must exceed ISF space by about 0.05 ml/g because of Na entry into myocytes, given that intracellular sodium is about 10 to 12 mM and cell water space is 0.55 ml/g.…”

“…We surmise that this phenomenon is due primarily to early septal contraction against no load. The resultant "shortening deactivation" reduces ATP requirements in the septum (58) relative to those in the free wall of the LV which contracts later and against more load. But there is still the question of why FDG uptake might be reduced even more than flow.…”

“…The early isotonic shortening induces "shortening deactivation", or what Brutsaert and colleagues (23-25) thought of as "load-dependent relaxation". This has been explored by David Allen (1,2) and pulled together in a quantitative comprehensive theoretical study by Landesberg and Sideman (58,59). Rapid shortening against low resistance causes reduction in the amount of calcium bound to myosin ATPase in the "strong" form, and reduces ATP hydrolysis.…”