Perturbed atrial calcium handling in an ovine model of heart failure: Potential roles for reductions in the L-type calcium current

Abstract

Heart failure (HF) is commonly associated with reduced cardiac output and an increased risk of atrial arrhythmias particularly during β-adrenergic stimulation. The aim of the present study was to determine how HF alters systolic Ca2 + and the response to β-adrenergic (β-AR) stimulation in atrial myocytes. HF was induced in sheep by ventricular tachypacing and changes in intracellular Ca2 + concentration studied in single left atrial myocytes under voltage and current clamp conditions. The following were all reduced in HF atrial myocytes; Ca2 + transient amplitude (by 46% in current clamped and 28% in voltage clamped cells), SR dependent rate of Ca2 + removal (kSR, by 32%), L-type Ca2 + current density (by 36%) and action potential duration (APD90 by 22%). However, in HF SR Ca2 + content was increased (by 19%) when measured under voltage-clamp stimulation. Inhibiting the L-type Ca2 + current (ICa-L) in control cells reproduced both the decrease in Ca2 + transient amplitude and increase of SR Ca2 + content observed in voltage-clamped HF cells. During β-AR stimulation Ca2 + transient amplitude was the same in control and HF cells. However, ICa-L remained less in HF than control cells whilst SR Ca2 + content was highest in HF cells during β-AR stimulation. The decrease in ICa-L that occurs in HF atrial myocytes appears to underpin the decreased Ca2 + transient amplitude and increased SR Ca2 + content observed in voltage-clamped cells.

Effect of Heart Failure:induced Electrical Remodeling on the Initiation of Atrial Arrhythmias

“…These simulation results were much smaller compared to the experimental observations by Clarke et al [3], who showed a reduction in APD90 by 22% and a reduction in the amplitude of systolic Ca 2+ transient by 46±17%. When cases of HF-2 and HF-3 were considered, the simulated results showed a reduction in effective refractory period (ERP) and APD90, which were opposite to the observation of Cha et al [4] and Li et al [5], who showed increases in both of them.…”

“…We used a set of cellular models of sheep atrial myocytes developed by Butters et al [8] that took into considerations of the intrinsic electrophysiological Table 1) under HF based on the experiment data of the sheep [3]. As data from sheep may be incomplete, we also assumed similar changes of ICaL, Ito, IKs and INCX as shown in canine HF atrial cells [4,5] as shown in cases of HF-2 and HF-3 in Table 1.…”

“…Atrial myocytes from sheep or canine hearts with HF induced by ventricular tachypacing showed reductions of the density of L-type Ca 2+ current (ICaL), transient outward K + current (Ito) and slow delayed rectifier current (IKs), and an increase of transient inward Na + /Ca 2+ exchanger (INCX) current compared with normal hearts [3][4][5][6]. In addition, HF has impact on atrial myocyte cellular Ca 2+ ]i release) and prolonged action potential duration (APD) in HF myocytes [7].…”

“…In addition, HF has impact on atrial myocyte cellular Ca 2+ ]i release) and prolonged action potential duration (APD) in HF myocytes [7]. On the contrary, Clarke et al showed a reduction in Ca 2+ transient, shortened APD and reduced Ca 2+ transient with an ovine model of HF [3]. All of these changes may contribute to abnormalities in the propagation of electrical excitation waves.…”

Methods for isolating atrial cells from large mammals and humans

“…The composition of the solutions used by our group can be found in Supplemental Table 1, and those of other groups in Supplemental Table 3. A Ca 2+ -free [109], low-Ca 2+ [61] or cardioplegic solution [35] is used for initial washing and enzyme perfusion. A taurine-containing low-Ca 2+ solution is used for final washing and tissue dissociation.…”