Compensatory and decompensatory alterations in cardiomyocyte Ca²⁺ dynamics in hearts with diastolic dysfunction following aortic banding

Abstract

Key pointsr At the cellular level cardiac hypertrophy causes remodelling, leading to changes in ionic channel, pump and exchanger densities and kinetics.r Previous studies have focused on quantifying changes in channels, pumps and exchangers without quantitatively linking these changes with emergent cellular scale functionality.r Two biophysical cardiac cell models were created, parameterized and validated and are able to simulate electrophysiology and calcium dynamics in myocytes from control sham operated rats and aortic-banded rats exhibiting diastolic dysfunction. r Results show that the ability to dynamically change systolic Ca 2+ , through changes in expression of key Ca 2+ modelling protein densities, is drastically reduced following the aortic banding procedure; however the cells are able to compensate Ca 2+ homeostasis in an efficient way to minimize systolic dysfunction.Abstract Elevated left ventricular afterload leads to myocardial hypertrophy, diastolic dysfunction, cellular remodelling and compromised calcium dynamics. At the cellular scale this remodelling of the ionic channels, pumps and exchangers gives rise to changes in the Ca 2+ transient. However, the relative roles of the underlying subcellular processes and the positive or negative impact of each remodelling mechanism are not fully understood. Biophysical cardiac cell models were created to simulate electrophysiology and calcium dynamics in myocytes from control rats (SHAM) and aortic-banded rats exhibiting diastolic dysfunction. The model parameters and framework were validated and the fitted parameters demonstrated to be unique for explaining our experimental data. The contribution of each ionic pathway to the calcium kinetics was calculated, identifying the L-type Ca 2+ channel (LCC) and the sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA) as the principal regulators of systolic and diastolic Ca 2+ , respectively. In the aortic banding model, the sensitivity of systolic Ca 2+ to LCC density and diastolic Ca 2+ to SERCA density decreased by 16-fold and increased by 23%, respectively, relative to the SHAM model. The energy cost of ionic homeostasis is maintained across the two models. The models predict that changes in ionic pathway densities in compensated aortic banding rats maintain Ca 2+ function and efficiency. The ability to dynamically alter systolic function is significantly diminished, while the capacity to maintain diastolic Ca 2+ is moderately increased.

Deterministic and Stochastic Cellular Mechanisms Contributing to Carbon Monoxide Induced Ventricular Arrhythmias

“…The three models we used are; the Gattoni et al, 2016 (rat) and Luo and Rudy, 1994 (guinea-pig) and O’Hara et al, 2011 human models were selected as being species appropriate, convenient, and fit for purpose. They, and their modifications, have been widely used so there is an extensive literature for comparison ( Viswanatahan and Rudy, 1999 ; Heijman at al., 2011 ; Cardona et al, 2016 ; Gattoni at al., 2017 ; Lee at al., 2017 ; Whittaker at al., 2017 ). Here we use the ORd (2011) model to predict pro- or anti-arrhythmogenic effects in adult human tissue, as CO poses issues in public health and clinical medicine and human in vitro and in vivo electrophysiological data is lacking.…”

In silico identification of potential calcium dynamics and sarcomere targets for recovering left ventricular function in rat heart failure with preserved ejection fraction

“…This rat model will be referred to as “SHAM” throughout the entire work. At the cellular level, ion fluxes and calcium dynamics were simulated using the Gattoni et al [ 5 ] model of rat left ventricular myocyte electrophysiology at 37° and 6 HZ pacing frequency. Active tension generation was described using the Land et al [ 6 ] model of sarcomere contraction, comprising thin and thick filament dynamics, and accounting for sarcomere-length and -velocity dependencies.…”

“…Briefly, we selected 8 compounds, which were well characterised for multiple ion channels and for which we could find whole organ measurements from literature, from the comprehensive in vitro proarrhythmia assay (CiPA) [ 19 ] official list, namely bepridil, chlorpromazine, diltiazem, mexiletine, nifedipine, ranolazine, sotalol and verapamil, and we described their action at the cell level using a 4-channel description, namely I Na , I to , I K1 and I CaL . I Kr channel was not included as it has a small amplitude in rats myocytes [ 20 ] and so was not included in the employed rat cell model [ 5 ].…”

“…By subtracting the obtained B values from 1, we obtained a matrix of scaling coefficients for the channels' conductances, representing the fractions of active channels in the presence of the compounds at different concentrations. We tested 13 equally-spaced compound concentrations (−log M) in the range [4,10] (extremes included), which corresponded to compound concentrations between 10 −10 M and 10 −4 M. We then run the Gattoni et al [5] model by scaling the ion channels conductances to simulate the action of different concentrations of each compound at the cell level and collected the resulting calcium PLOS COMPUTATIONAL BIOLOGY transients (last beat curves of limit cycle, 5000 beats simulations). An example of calcium transients obtained after simulating the effect of verapamil is provided in S4 Text.…”

Predicting left ventricular contractile function via Gaussian process emulation in aortic-banded rats

“…Previous heart models have shown that heterogeneous activation patterns have negligible impact in the small rat heart [11]. Rat ventricular myocytes' Ca 2+ transient was described using the Gattoni et al models [14] for SHAM and AB rats hearts at 37 • C and 6 Hz pacing frequency. Rat cellular contraction was modelled using the Land et al [11] model to simulate tension generation arising from the thin and thick filaments.…”