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Compensatory and decompensatory alterations in cardiomyocyte Ca(2+) dynamics in hearts with diastolic dysfunction following aortic banding

Research output: Contribution to journalArticle

Sara Gattoni, Åsmund Treu Røe, Jan Magnus Aronsen, Ivar Sjaastad, William E. Louch, Nicolas P. Smith, Steven A. Niederer

Original languageEnglish
JournalThe Journal of physiology
DOIs
StatePublished - 21 May 2017

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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 Ca(2+) channel and sarco/endoplasmic reticulum Ca(2+) ATPase as the principal regulators of systolic and diastolic Ca(2+) , respectively. 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.

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