Experimental assessment of a myocyte-based multiscale model of cardiac contractile dysfunction

LASCANO, ELENA C.; FELICE, JUAN I.; WRAY, SANDRA; KOSTA, SARA; DAUBY, PIERRE C.; CABRERA-FISCHER, EDMUNDO I.; NEGRONI, JORGE A.

JOURNAL OF THEORETICAL BIOLOGY

ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD

Año: 2018 vol. 456 p. 16 - 28

0022-5193

Cardiac contractile dysfunction (CD) is amultifactorial syndrome caused by different acute or progressive diseases whichhamper assessing the role of the underlying mechanisms characterizing a definedpathological condition. Mathematical modeling can help to understand theprocesses involved in CD and analyze their relative impact in the overall response.The aim of this study was thus to use a myocyte-based multiscale model of thecirculatory system to simulate the effects of halothane, a volatile anestheticwhich at high doses elicits significant acute CD both in isolated myocytes andintact animals. Ventricular chambers built using a human myocyte model wereincorporated into a whole circulatory system represented by resistances andcapacitances. Halothane-induced decreased sarco(endo)plasmic reticulum Ca2+(SERCA2a) reuptake pump, transient outward K+ (Ito), Na+-Ca2+ exchanger (INCX)and L-type Ca2+ channel (ICaL) currents, together with ryanodine receptor(RyR2) increased open probability (Po) and reduced myofilament Ca2+sensitivity, reproduced equivalent decreased action potential duration at 90%repolarization and intracellular Ca2+ concentration at the myocyte levelreported in the literature. In the whole circulatory system, model reduction inmean arterial pressure, cardiac output and regional wall thickening fractionwas similar to experimental results in open-chest sheep subjected to acutehalothane overdose. Effective model performance indicates that the modelstructure could be used to study other changes in myocyte targets eliciting CD.