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

Cardiac contractile dysfunction (CD) is a multifactorial syndrome caused by different acute or progressive diseases which hamper assessing the role of the underlying mechanisms characterizing a defined pathological condition. Mathematical modeling can help to understand the processes 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 the circulatory system to simulate the effects of halothane, a volatile anesthetic which at high doses elicits significant acute CD both in isolated myocytes and intact animals. Ventricular chambers built using a human myocyte model were incorporated into a whole circulatory system represented by resistances and capacitances. 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 level reported in the literature. In the whole circulatory system, model reduction in mean arterial pressure, cardiac output and regional wall thickening fraction was similar to experimental results in open-chest sheep subjected to acute halothane overdose. Effective model performance indicates that the model structure could be used to study other changes in myocyte targets eliciting CD.

Assessment of ventricular contractility and ventricular-arterial coupling with a model-based sensor.

Estimation of ventricular contractility and ventricular arterial coupling is clinically important in diagnosing and treating cardiac dysfunction in the critically ill. However, experimental assessment of indexes of ventricular contractility, such as the end-systolic pressure-volume relationship, requires a highly invasive maneuver and measurements that are not typical in an intensive care unit (ICU). This research describes the use of a previously validated cardiovascular system model and parameter identification process to evaluate the right ventricular arterial coupling in septic shock. Model-based ventricular arterial coupling is defined by the ratio of the end systolic right ventricular elastance (E(esrvf)) over the pulmonary artery elastance (E(pa)) or the mean pulmonary inflow resistance (R(pulin)). Results are compared to the clinical gold-standard assessment (conductance catheter method). Six anesthetized healthy pigs weighing 20-30kg received a 0.5mg kg(-1) endotoxin infusion over a period of 30min from T0 to T30, to induce septic shock and veno-venous hemofiltration was used from T60 onward. The results show good agreement with the gold-standard experimental assessment. In particular, the model-based right ventricular elastance (E(esrvf)) correlates well with the clinical gold standard (R(2)=0.69) and the model-based non-invasive coupling (E(esrvf)/R(pulin)) follow the same trends and dynamics (R(2)=0.37). The overall results show the potential to develop a model-based sensor to monitor ventricular-arterial coupling in clinical real-time.