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Published on: May 19, 2017
Intracellular Ca alternans: coordinated regulation by sarcoplasmic reticulum release, uptake, and leak
Lai-Hua Xie1, Daisuke Sato, Alan Garfinkel
1Cardiovascular Research Laboratory, Department of Medicine (Cardiology), David Geffen School of Medicine at the University of California, Los Angeles, California 90095, USA.
Insights
Beat-to-beat alternations in cardiac intracellular calcium (Ca(i)) transients can cause action potential alternans, promoting arrhythmias. Our study reveals that sarcoplasmic reticulum (SR) Ca release, uptake, and leak all influence Ca(i) alternans onset.
Area of Science:
- Cardiology
- Computational Biology
- Molecular Cardiology
Background:
- Beat-to-beat alternation in cardiac intracellular calcium (Ca(i)) transients is a known driver of action potential duration alternans.
- This phenomenon creates a substrate highly prone to cardiac arrhythmias.
- While experimental studies highlight the role of sarcoplasmic reticulum (SR) Ca release dependence on SR Ca load, theoretical predictions suggest other factors are also crucial.
Purpose of the Study:
- To investigate the coordinated effects of SR Ca release, uptake, and leak on the initiation of Ca(i) alternans.
- To compare theoretical predictions with experimental data from cardiac myocytes.
Main Methods:
- Utilized an iterated map analysis to model the dynamics of Ca(i) alternans.
- Performed numerical simulations with a realistic action potential model.
- Conducted AP clamp experiments on isolated rabbit ventricular myocytes.
Main Results:
- SR Ca release, uptake, and leak were found to have independent direct effects influencing Ca(i) alternans.
- Release and leak promote Ca(i) alternans, while uptake suppresses it.
- The net balance of direct and indirect effects, mediated by alterations in SR Ca load, determines the overall impact on alternans.
Conclusions:
- BayK8644 promotes Ca(i) alternans by increasing SR Ca load and release fraction.
- Adenoviral SERCA2a overexpression, ryanodine, and FK506 suppress Ca(i) alternans by modulating SR Ca uptake and leak.
- Understanding these coordinated effects is vital for managing arrhythmogenic substrates.
Abstract:
Beat-to-beat alternation in the cardiac intracellular Ca (Ca(i)) transient can drive action potential (AP) duration alternans, creating a highly arrhythmogenic substrate. Although a steep dependence of fractional sarcoplasmic reticulum (SR) Ca release on SR Ca load has been shown experimentally to promote Ca(i) alternans, theoretical studies predict that other factors are also important. Here we present an iterated map analysis of the coordinated effects of SR Ca release, uptake, and leak on the onset of Ca(i) alternans. Predictions were compared to numerical simulations using a physiologically realistic AP model as well as to AP clamp experiments in isolated patch-clamped rabbit ventricular myocytes exposed to 1), the Ca channel agonist BayK8644 (100 nM) to increase SR Ca load and release fraction, 2), overexpression of an adenoviral SERCA2a construct to increase SR Ca uptake, and 3), low-dose FK506 (20 microM) or ryanodine (1 microM) to increase SR Ca leak. Our findings show that SR Ca release, uptake, and leak all have independent direct effects that promote (release and leak) or suppress (uptake) Ca(i) alternans. However, since each factor affects the other by altering SR Ca load, the net balance of their direct and indirect effects determines whether they promote or suppress alternans. Thus, BayK8644 promotes, whereas Ad-SERCA2a overexpression, ryanodine, and FK506 suppress, Ca(i) alternans under AP clamp conditions.
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