A Quantitative Analysis of Cardiac Myocyte Relaxation: A Simulation Study

Abstract

The determinants of relaxation in cardiac muscle are poorly understood, yet compromised relaxation accompanies various pathologies and impaired pump function. In this study, we develop a model of active contraction to elucidate the relative importance of the [Ca2+]i transient magnitude, the unbinding of Ca2+ from troponin C (TnC), and the length-dependence of tension and Ca2+ sensitivity on relaxation. Using the framework proposed by one of our researchers, we extensively reviewed experimental literature, to quantitatively characterize the binding of Ca2+ to TnC, the kinetics of tropomyosin, the availability of binding sites, and the kinetics of crossbridge binding after perturbations in sarcomere length. Model parameters were determined from multiple experimental results and modalities (skinned and intact preparations) and model results were validated against data from length step, caged Ca2+, isometric twitches, and the half-time to relaxation with increasing sarcomere length experiments. A factorial analysis found that the [Ca2+]i transient and the unbinding of Ca2+ from TnC were the primary determinants of relaxation, with a fivefold greater effect than that of length-dependent maximum tension and twice the effect of tension-dependent binding of Ca2+ to TnC and length-dependent Ca2+ sensitivity. The affects of the [Ca2+]i transient and the unbinding rate of Ca2+ from TnC were tightly coupled with the effect of increasing either factor, depending on the reference [Ca2+]i transient and unbinding rate.

Regression Analysis of the Left-ventricular Isochoric Pressure Decay of the Heart: Four or Five Model Parameters?

“…Biophysical "bottom up" models usually consider much more factors even to describe the behaviour of the myocardial fiber, such as 22 parameters for contraction and relaxation 1 . Transforming this one dimensional tension to intracaval pressure requires even more (spatiotemporal) parameters among which the anatomical orientation of the myofibrils takes a significant influence on the pressure relaxation curve 11 .…”

Alya: Multiphysics engineering simulation toward exascale

“…The mechanical deformation is the result of the active tension generated by the myocytes as accounted for in 3.2. The model assumes that the active stress is produced only in the direction of the fiber and depends only on the calcium concentration of the cardiac cell [22]:…”

Cardiac cell modelling: Observations from the heart of the cardiac physiome project

“…More recently, detailed biophysical models of the inner workings of the sarcomere have emerged. These models are now capable of facilitating the investigation of the mechanisms responsible for relaxation (Niederer et al 2006), heterogeneous tension development (Campbell et al 2009) and cooperative activation ).…”

“…More recent models have aimed to capture both thick and thin filament kinetics (Razumova et al 1999, Sachse et al 2003, Niederer et al 2006, Schneider et al 2006, Rice et al 2008. In most cases these models are represented by systems of ordinary differential equations, and potential spatial effects are included in phenomenological representations or are ignored.…”

“…The scarcity of experimental data for different species at physiological temperatures restricts the development of models and limits the confidence that model conclusions are correct or relevant at 37 o C. Models can either aim to simulate contraction at room temperature (Niederer et al 2006), scale parameters (Rice et al 2008) using the temperature coefficient Q 10 (Hille 2001), or ignore temperature effects altogether. More recently experimental measurements of contraction are becoming available at 37 o C in trabeculae (Varian et al 2006) and isolated single cell preparations (Iribe et al 2007).…”