Abstract
Ventricular contraction is roughly proportional to the amount of calcium released from the Sarcoplasmic Reticulum (SR) during systole. While it is rather straightforward to measure calcium levels and contractibility under different physiological conditions, the complexity of calcium handling during systole and diastole has made the prediction of its release at steady state impossible. Here we approach the problem analyzing the evolution of intracellular and extracellular calcium fluxes during a single beat which is away from homeostatic balance. Using an in-silico subcellular model of rabbit ventricular myocyte, we show that the high dimensional nonlinear problem of finding the steady state can be reduced to a two-variable general equilibrium condition where pre-systolic calcium level in the cytosol and in the SR must fulfill simultaneously two different equalities. This renders calcium homeostasis as a problem that can be studied in terms of its equilibrium structure, leading to precise predictions of steady state from single-beat measurements. We show how changes in ion channels modify the general equilibrium, as shocks would do in general equilibrium macroeconomic models. This allows us to predict when an enhanced entrance of calcium in the cell reduces its contractibility and explain why SERCA gene therapy, a change in calcium handling to treat heart failure, might fail to improve contraction even when it successfully increases SERCA expression.
Highlights
Complex systems often present robust regulation that makes them resilient to changes in environmental conditions
Using an in-silico subcellular model of rabbit ventricular myocyte, we show that the high dimensional nonlinear problem of finding the steady state can be reduced to a two-variable general equilibrium condition where pre-systolic calcium level in the cytosol and in the sarcoplasmic reticulum (SR) must fulfill simultaneously two different equalities
Cardiomyocytes, upon voltage excitation, release calcium, which leads to cell contraction
Summary
Complex systems often present robust regulation that makes them resilient to changes in environmental conditions. The maintenance of homeostatic equilibrium in temperature, pH, osmolality or ionic concentration is crucial to sustaining life, and complex feedback mechanisms have been developed to achieve such goal Another important example is the regulation of heart function. Once the voltage is repolarized, calcium released from the SR is uptaken by SERCA back to the SR while the sodium-calcium exchanger (NCX) is able to extrude the calcium which entered via LCC, and contraction ceases. This process seems universal across species, quantitatively can be very different. Translation of results obtained in animal models targeting different regulatory pathways into human patients is not trivial
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