Figure 1.

Remodelling of intracellular Ca²⁺cycling during heart failure (HF) progression. (A) Representative Ca²⁺ transients recorded in control as well as in ventricular myocytes isolated from hearts with early and advanced stages of HF. (B) Representative action potential (AP) traces (top) along with corresponding line scan images of Fluo-3 fluorescence (middle) and Ca²⁺ transients ([Ca²⁺]_c; bottom) recorded during β-adrenergic receptor stimulation in the three different types of cardiomyocytes. Arrows indicate delayed after-depolarizations. Red arrow points to extrasystolic AP. (C) Summary graphs illustrate that progression of HF is associated with early and progressive increase in the rate of SR Ca²⁺ leak (red line). The amplitude of Ca²⁺ transients recorded under baseline conditions (black line) decreases with significant time-delay in respect to elevation of leak during the onset of HF. Such relationships are attributable to the capacity of myocyte Ca²⁺ handling for autoregulation until SR is depleted by a drastic increase in the SR Ca²⁺ leak (see text for detailed explanation). In contrast, the frequency of diastolic Ca²⁺ waves recorded in the presence of β-adrenergic agonist isoproterenol (ISO) (brown line) parallels increases in the SR Ca²⁺ leak. Ca²⁺ waves facilitate diastolic SR Ca²⁺ loss resulting in decrease in Ca²⁺ transient amplitude (+ISO; purple line). Note that in advanced stages of HF persistent cytosolic Ca²⁺ oscillations effectively uncouple electrical excitation from mechanical response. Progressive alterations in Ca²⁺ cycling in HF are coupled to sequential modification of RyR2 by CaMKII-dependent phosphorylation (blue line) and oxidation (green line). Adapted from Belevych et al.²⁷