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Using a Failing Human Ventricular Cardiomyocyte Model to Re-Evaluate Ca2+ Cycling, Voltage Dependence, and Spark
Jerome Anthony E Alvarez1,2, Mohsin Saleet Jafri1,3, Aman Ullah1
1School of Systems Biology, George Mason University, Fairfax, VA 22030, USA.
Insights
Heart failure involves altered calcium handling and ion currents. This study models these changes, revealing that both sarcoplasmic reticulum calcium ATPase (SERCA) and ryanodine receptor (RyR2) dysfunction significantly contribute to calcium mishandling and heart failure progression.
Area of Science:
- Cardiovascular Physiology
- Computational Biology
- Biophysics
Background:
- Heart failure (HF) is characterized by impaired excitation-contraction (EC) coupling, including prolonged action potentials and altered calcium (Ca2+) transients.
- Key molecular changes in HF include downregulated potassium (K+) currents, reduced sarcoplasmic reticulum Ca2+ ATPase (SERCA), increased ryanodine receptor (RyR2) sensitivity, and upregulated sodium-calcium exchanger (NCX).
Purpose of the Study:
- To computationally model human ventricular myocytes in heart failure to elucidate the relative contributions of altered calcium handling and membrane currents to EC coupling dysfunction.
- To investigate the impact of spontaneous Ca2+ release from the sarcoplasmic reticulum (SR) in the context of HF.
Main Methods:
- Development of a computational human ventricular myocyte model incorporating known HF-related alterations in ion currents and Ca2+ handling.
- Simulation of myocyte behavior under current-clamp and voltage-clamp conditions to assess Ca2+ dynamics and EC coupling gain.
Main Results:
- Reduced transient outward K+ current (Ito) significantly impacts RyR2 open probability and L-type calcium channel (LCC) density, affecting action potential duration.
- Under current-clamp, RyR2 hyperphosphorylation led to reduced SR Ca2+ release but prolonged Ca2+ sparks.
- Under voltage-clamp, decreased SERCA and upregulated NCX resulted in less SR Ca2+ uptake and lower EC coupling gain compared to HF with hyperphosphorylated RyR2s.
Conclusions:
- Combined dysfunction of SERCA and NCX, alongside RyR2 abnormalities, significantly contributes to Ca2+ mishandling at the spark level.
- Downregulation of cardiomyocyte potassium currents is a critical factor influencing RyR2 activity and action potential dynamics in HF.
- These integrated cellular mechanisms collectively drive the progression of heart failure through impaired Ca2+ handling.
Abstract:
Previous studies have observed alterations in excitation-contraction (EC) coupling during end-stage heart failure that include action potential and calcium (Ca2+) transient prolongation and a reduction of the Ca2+ transient amplitude. Underlying these phenomena are the downregulation of potassium (K+) currents, downregulation of the sarcoplasmic reticulum Ca2+ ATPase (SERCA), increase Ca2+ sensitivity of the ryanodine receptor, and the upregulation of the sodium-calcium (Na=-Ca2+) exchanger. However, in human heart failure (HF), debate continues about the relative contributions of the changes in calcium handling vs. the changes in the membrane currents. To understand the consequences of the above changes, they are incorporated into a computational human ventricular myocyte HF model that can explore the contributions of the spontaneous Ca2+ release from the sarcoplasmic reticulum (SR). The reduction of transient outward K+ current (Ito) is the main membrane current contributor to the decrease in RyR2 open probability and L-type calcium channel (LCC) density which emphasizes its importance to phase 1 of the action potential (AP) shape and duration (APD). During current-clamp conditions, RyR2 hyperphosphorylation exhibits the least amount of Ca2+ release from the SR into the cytosol and SR Ca2+ fractional release during a dynamic slow-rapid-slow (0.5-2.5-0.5 Hz) pacing, but it displays the most abundant and more lasting Ca2+ sparks two-fold longer than a normal cell. On the other hand, under voltage-clamp conditions, HF by decreased SERCA and upregulated INCX show the least SR Ca2+ uptake and EC coupling gain, as compared to HF by hyperphosphorylated RyR2s. Overall, this study demonstrates that the (a) combined effect of SERCA and NCX, and the (b) RyR2 dysfunction, along with the downregulation of the cardiomyocyte's potassium currents, could substantially contribute to Ca2+ mishandling at the spark level that leads to heart failure.
