Contractile-based model interpretation of pressure-volume dynamics in the constantly activated (Ba2+) isolated heart

Abstract

A contractile-based model was constructed to represent responses to changes in left ventricular (LV) volume in a heart with constantly activated myocardium. Hearts were isolated from rabbits, the myocardium was put into a state of constant activation by perfusion with Krebs Henseleit solution containing 0.5 mM Ba2+, and recordings were taken of LV pressure responses to step and sinusoidal changes in LV volume. Pressure responses to volume steps were divided into five characteristic phases. An elastance frequency spectrum was calculated from pressure responses to sinusoidal volume changes. Values of features of the elastance frequency spectrum were in accord with values of corresponding features of the step response. Using an explicit homology between elements responsible for LV pressure development (pressure generators) and elements responsible for muscle force development (myofilament cross-bridges), mathematical models were constructed to re-create the data. Basic assumptions were that (1) pressure was the summed effect of pressure generators undergoing volumetric distortion; (2) changes in volume brought about changes in both generator numbers (recruitment) and generator distortion; (3) pressure generators cycle through states that variously do and do not generate pressure. An initial two-step model included a cycle with one attachment step and one detachment step between non-pressure-bearing and pressure-bearing states. Predictions by the two-step model had many similarities with the experimental observations, but were lacking in some important respects. The two-step model was upgraded to a multiple-step model. In addition to multiple attachment and detachment steps within the cycle, the multiple-step model incorporated distortion-dependent detachment steps. The multiple-step model re-created all aspects of the experimentally observed step and frequency responses. Furthermore, this model was consistent with current theories of contractile processes.