Abstract
Key points At the cellular level cardiac hypertrophy causes remodelling, leading to changes in ionic channel, pump and exchanger densities and kinetics.Previous studies have focused on quantifying changes in channels, pumps and exchangers without quantitatively linking these changes with emergent cellular scale functionality.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.The contribution of each ionic pathway to the calcium kinetics was calculated, identifying the L‐type Ca2+ channel and sarco/endoplasmic reticulum Ca2+ATPase as the principal regulators of systolic and diastolic Ca2+, respectively.Results show that the ability to dynamically change systolic Ca2+, through changes in expression of key Ca2+ modelling protein densities, is drastically reduced following the aortic banding procedure; however the cells are able to compensate Ca2+ homeostasis in an efficient way to minimize systolic dysfunction. 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 Ca2+ 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 Ca2+ channel (LCC) and the sarco/endoplasmic reticulum Ca2+‐ATPase (SERCA) as the principal regulators of systolic and diastolic Ca2+, respectively. In the aortic banding model, the sensitivity of systolic Ca2+ to LCC density and diastolic Ca2+ 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 Ca2+ function and efficiency. The ability to dynamically alter systolic function is significantly diminished, while the capacity to maintain diastolic Ca2+ is moderately increased.
Highlights
Heart failure (HF) due to left ventricular pressure overload following aortic stenosis or hypertension, remains a serious public health problem, associated with high morbidity and mortality (Drazner, 2011)
For each model we identified how many of experimental phenotypes (peak calcium concentration (PCa), diastolic Ca2+ levels (DCa), relaxation time at 50% decay (RT50) and time to peak Ca2+ (Tpeak)) the model matched and we ranked models based on this number (1–4)
Simulated sarcoplasmic reticulum (SR) Ca2+ content in the AB model at 6 Hz was increased by 61% compared with the simulated value in the SHAM model, due to increased sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) activity
Summary
Heart failure (HF) due to left ventricular pressure overload following aortic stenosis or hypertension, remains a serious public health problem, associated with high morbidity and mortality (Drazner, 2011). It is commonly believed that cardiac hypertrophy develops in response to increased left ventricular afterload This increased pressure, in turn, generates increased load on the myocardial wall and leads to tissue and cellular remodelling. An electrical wave of depolarization spreads rapidly through the myocardium inducing an intracellular Ca2+ influx through the voltage dependent L-type Ca2+ channels (LCCs) (Hobai & Levi, 1999) triggering the release of more Ca2+ from ryanodine receptors (RyRs) in the sarcoplasmic reticulum (SR) (Fabiato & Fabiato, 1979; Sham et al 1995) This resultant increase in cytosolic Ca2+ concentration induces contraction at the level of the myofilaments.
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