Dysregulated Calcium Handling in Cirrhotic Cardiomyopathy

Abstract

Cirrhotic cardiomyopathy is a syndrome of blunted cardiac systolic and diastolic function in patients with cirrhosis. However, the mechanisms remain incompletely known. Since contractility and relaxation depend on cardiomyocyte calcium transients, any factors that impact cardiac contractile and relaxation functions act eventually through calcium transients. In addition, calcium transients play an important role in cardiac arrhythmias. The present review summarizes the calcium handling system and its role in cardiac function in cirrhotic cardiomyopathy and its mechanisms. The calcium handling system includes calcium channels on the sarcolemmal plasma membrane of cardiomyocytes, the intracellular calcium-regulatory apparatus, and pertinent proteins in the cytosol. L-type calcium channels, the main calcium channel in the plasma membrane of cardiomyocytes, are decreased in the cirrhotic heart, and the calcium current is decreased during the action potential both at baseline and under stimulation of beta-adrenergic receptors, which reduces the signal to calcium-induced calcium release. The study of sarcomere length fluctuations and calcium transients demonstrated that calcium leakage exists in cirrhotic cardiomyocytes, which decreases the amount of calcium storage in the sarcoplasmic reticulum (SR). The decreased storage of calcium in the SR underlies the reduced calcium released from the SR, which results in decreased cardiac contractility. Based on studies of heart failure with non-cirrhotic cardiomyopathy, it is believed that the calcium leakage is due to the destabilization of interdomain interactions (dispersion) of ryanodine receptors (RyRs). A similar dispersion of RyRs may also play an important role in reduced contractility. Multiple defects in calcium handling thus contribute to the pathogenesis of cirrhotic cardiomyopathy.

Keywords: L-type calcium channel; calcium transient; cardiac contractility; cirrhotic cardiomyopathy; ryanodine receptors.

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 I_Kr 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 (I_Na) corresponding with the start of the QRS complex on the ECG. Phase 1: closure of the sodium channels. Short transient outward current (I_to) 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 (I_Kur and I_Ks). Phase 3: repolarization due to closure of the L-type calcium channels and outward potassium currents (I_Ks and I_Kr) 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]).

Figure 2

Calcium transients in cardiomyocytes.

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]).

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 RMS_SL 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]).

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/F_o). 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]).