Dysregulated Calcium Handling in Cirrhotic Cardiomyopathy

Figures

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  Figure 1. Action potential of ventricular myocardium (A) and corresponding electrocardiogram (ECG) (B). Example of a normal ventricular myocardial action potential with normal QT interval (black line) and a prolonged ventricular action potential due to an IKr block resulting in a prolonged phase 2 and 3 of the action potential and prolonged QT interval (red line). Phase 0: rapid depolarization mediated by voltage-gated sodium channels (INa) corresponding with the start of the QRS complex on the ECG. Phase 1: closure of the sodium channels. Short transient outward current (Ito) mediated by voltage-gated potassium channels. Phase 2: plateau phase due to an equilibrium between the inward calcium current by L-type calcium channels and an outward potassium current (IKur and IKs). Phase 3: repolarization due to closure of the L-type calcium channels and outward potassium currents (IKs and IKr) corresponding to the end of the T-wave on the ECG. Phase 4: a slow depolarization occurs if the current reaches the threshold, which initiates the next depolarization (Reproduced from Lee W. et al. [19]).

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  Figure 2. Calcium transients in cardiomyocytes.

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  Figure 3. Calcium kinetics in BDL-cirrhotic and control cardiomyocytes. Comparison of L-type Ca2+ current densities from ventricular myocytes of BDL- and sham-treated animals. (A) Representative currents elicited by a depolarizing step to +10 mV from a conditioning potential of −40 mV. All currents were corrected for cell capacitance and expressed as current densities. (B) Current–voltage relationships were constructed by depolarizing steps to test potentials between −60 and +70 mV from the conditioning potential of −40 mV for myocytes isolated from BDL-treated (n = 19; O) and sham-operated (n = 16; ●) animals (Reproduced from Ward CA et al. [17]).

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  Figure 4. Spontaneous sarcomere activity in sham-control and BDL-cirrhotic rat ventricular trabeculae and spontaneous sarcomere fluctuation at 26 °C during the end-diastolic period in trabeculae at stimulus rates from 0.2 to 1 Hz. Open symbols are the mean ± SEM of RMSSL and lines represent the linear relation between the frequency of stimulation and the amount of spontaneous sarcomere activity. [Ca2+]o was 0.5 mmol/L; n = 5. BDL-cirrhotic trabeculae show significantly greater spontaneous sarcomere fluctuation, suggesting increased calcium leakage (Reproduced from Honar H. et al. [16]).

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  Figure 5. Force generation and calcium kinetics in isolated ventricular trabeculae from BDL-cirrhotic and control rat hearts. (A): Ca2+ transient fluorescence in isolated myocytes during steady-state contraction at a stimulus rate of 0.5 Hz at varied [Ca2+]o in diastole (minimum transient) and systole (maximum F/Fo). BDL-cirrhotic trabeculae generate less minimum and maximum contractile force throughout the range of stimulation. (B): Time-to-peak Ca2+ transient (TTP) and time for Ca2+ transient to return to half maximum (THR). Data are the mean ± SEM of 51–58 myocytes per group. * p < 0.05 and *** p < 0.001 compared to the corresponding sham group. Calcium transients are decreased in cirrhotic trabeculae compared to controls (Reproduced from Honar H. et al. [16]).