Showing papers by "David A. Eisner published in 2022"
4 citations
TL;DR: In this article , sarcoplasmic reticulum (SR) Ca2+ content reaches a threshold and is commonly induced experimentally by raising external Ca2+, although the mechanism by which this causes waves is unclear and was the focus of this study.
Abstract: Ventricular arrhythmias can cause death in heart failure (HF). A trigger is the occurrence of Ca2+ waves which activate a Na+‐Ca2+ exchange (NCX) current, leading to delayed after‐depolarisations and triggered action potentials. Waves arise when sarcoplasmic reticulum (SR) Ca2+ content reaches a threshold and are commonly induced experimentally by raising external Ca2+, although the mechanism by which this causes waves is unclear and was the focus of this study. Intracellular Ca2+ was measured in voltage‐clamped ventricular myocytes from both control sheep and those subjected to rapid pacing to produce HF. Threshold SR Ca2+ content was determined by applying caffeine (10 mM) following a wave and integrating wave and caffeine‐induced NCX currents. Raising external Ca2+ induced waves in a greater proportion of HF cells than control. The associated increase of SR Ca2+ content was smaller in HF due to a lower threshold. Raising external Ca2+ had no effect on total influx via the L‐type Ca2+ current, ICa‐L, and increased efflux on NCX. Analysis of sarcolemmal fluxes revealed substantial background Ca2+ entry which sustains Ca2+ efflux during waves in the steady state. Wave frequency and background Ca2+ entry were decreased by Gd3+ or the TRPC6 inhibitor BI 749327. These agents also blocked Mn2+ entry. Inhibiting connexin hemi‐channels, TRPC1/4/5, L‐type channels or NCX had no effect on background entry. In conclusion, raising external Ca2+ induces waves via a background Ca2+ influx through TRPC6 channels. The greater propensity to waves in HF results from increased background entry and decreased threshold SR content.
3 citations
TL;DR: In this paper , the authors show that despite reduced transverse (t)-tubule density due to immature t-tubules, the newborn atrium is highly specialised to maintain Ca2+ release.
3 citations
TL;DR: The data suggests loss of t-tubules, decreased Ca release at triggered and propagated sites and RyR cluster remodelling all contribute to the decrease in the atrial systolic Ca transient and dyssynchrony observed in HF.
Abstract: Background: Transverse (t)-tubules enable close coupling between L-type calcium (Ca) channels and ryanodine receptors (RyR) to facilitate triggered Ca release throughout the cell. In heart failure (HF) there is disruption of the t-tubule network that contributes to dyssynchronous Ca release. Despite the importance of t-tubules in triggering Ca release in the atria of large mammals, little is known about Ca release sites and how they are altered in HF. Objective: To investigate Ca release in the healthy and failing sheep atria and examine how this may be contributed to by ttubule and RyR remodelling. Methods: HF was induced in sheep by right ventricular tachypacing and left atrial myocytes isolated from control and HF animals. Cells were loaded with fluo-3 and stimulated under current clamp control. RyR structure was assessed using stochastic optical reconstruction microscopy (STORM). Results: In control atrial myocytes, triggered Ca release occurred at discrete sites on the surface and in the centre of the cell associated with t-tubules. In HF, t-tubule loss was accompanied by a reduction in central Ca release sites. As such, triggered Ca release was restricted to the cell surface with central Ca release decreased and reliant on propagation. Ca transient amplitude was decreased in both triggered and propagated sites in HF, and the difference between triggered and propagated release was exacerbated. The coefficient of variation for Ca release was greater in HF indicating variable amplitude of release between beats. As RyR cluster properties can influence Ca release, their structure was assessed. Atrial RyRs predominantly localise to the z-line but also to the cell surface. Compared to control, RyR clusters were smaller, more fragmented and further apart in HF which could perturb both triggered and propagated Ca release. Conclusion: Our data suggests loss of t-tubules, decreased Ca release at triggered and propagated sites and RyR cluster remodelling all contribute to the decrease in the atrial systolic Ca transient and dyssynchrony observed in HF.
TL;DR: The data suggests loss of t-tubules, decreased Ca release at triggered and propagated sites and RyR cluster remodelling all contribute to the decrease in the atrial systolic Ca transient and dyssynchrony observed in HF.
Abstract: Background: Transverse (t)-tubules enable close coupling between L-type calcium (Ca) channels and ryanodine receptors (RyR) to facilitate triggered Ca release throughout the cell. In heart failure (HF) there is disruption of the t-tubule network that contributes to dyssynchronous Ca release. Despite the importance of t-tubules in triggering Ca release in the atria of large mammals, little is known about Ca release sites and how they are altered in HF. Objective: To investigate Ca release in the healthy and failing sheep atria and examine how this may be contributed to by ttubule and RyR remodelling. Methods: HF was induced in sheep by right ventricular tachypacing and left atrial myocytes isolated from control and HF animals. Cells were loaded with fluo-3 and stimulated under current clamp control. RyR structure was assessed using stochastic optical reconstruction microscopy (STORM). Results: In control atrial myocytes, triggered Ca release occurred at discrete sites on the surface and in the centre of the cell associated with t-tubules. In HF, t-tubule loss was accompanied by a reduction in central Ca release sites. As such, triggered Ca release was restricted to the cell surface with central Ca release decreased and reliant on propagation. Ca transient amplitude was decreased in both triggered and propagated sites in HF, and the difference between triggered and propagated release was exacerbated. The coefficient of variation for Ca release was greater in HF indicating variable amplitude of release between beats. As RyR cluster properties can influence Ca release, their structure was assessed. Atrial RyRs predominantly localise to the z-line but also to the cell surface. Compared to control, RyR clusters were smaller, more fragmented and further apart in HF which could perturb both triggered and propagated Ca release. Conclusion: Our data suggests loss of t-tubules, decreased Ca release at triggered and propagated sites and RyR cluster remodelling all contribute to the decrease in the atrial systolic Ca transient and dyssynchrony observed in HF.