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

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 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.