Showing papers by "David A. Eisner published in 2017"

Calcium and Excitation-Contraction Coupling in the Heart.

Abstract: Cardiac contractility is regulated by changes in intracellular Ca concentration ([Ca 2+ ] i ). Normal function requires that [Ca 2+ ] i be sufficiently high in systole and low in diastole. Much of the Ca needed for contraction comes from the sarcoplasmic reticulum and is released by the process of calcium-induced calcium release. The factors that regulate and fine-tune the initiation and termination of release are reviewed. The precise control of intracellular Ca cycling depends on the relationships between the various channels and pumps that are involved. We consider 2 aspects: (1) structural coupling: the transporters are organized within the dyad, linking the transverse tubule and sarcoplasmic reticulum and ensuring close proximity of Ca entry to sites of release. (2) Functional coupling: where the fluxes across all membranes must be balanced such that, in the steady state, Ca influx equals Ca efflux on every beat. The remainder of the review considers specific aspects of Ca signaling, including the role of Ca buffers, mitochondria, Ca leak, and regulation of diastolic [Ca 2+ ] i .

Systolic [Ca2+ ]i regulates diastolic levels in rat ventricular myocytes.

Abstract: [Ca2+]i must be low enough in diastole so that the ventricle is relaxed and can refill with blood. Interference with this will impair relaxation. The factors responsible for regulation of diastolic [Ca2+]i, in particular the relative roles of the sarcoplasmic reticulum (SR) and surface membrane are unclear. We investigated the effects on diastolic [Ca2+]i that result from the changes of Ca cycling known to occur in heart failure. Experiments were performed using Fluo-3 in voltage-clamped rat ventricular myocytes. Increasing stimulation frequency increased diastolic [Ca2+]i. This increase of [Ca2+]i was larger when SR function was impaired either by making the RyR leaky (with caffeine or ryanodine) or by decreasing SERCA activity with thapsigargin. The increase of diastolic [Ca2+]i produced by interfering with the SR was accompanied by a decrease of the amplitude of the systolic Ca transient such that there was no change of time-averaged [Ca2+]i. Time-averaged [Ca2+]i was increased by β-adrenergic stimulation with isoprenaline and increased in a saturating manner with increased stimulation frequency; average [Ca2+]i was a linear function of Ca entry per unit time. Diastolic and time-averaged [Ca2+]i were decreased by decreasing the L-type Ca current (with 50 μm cadmium chloride). We conclude that diastolic [Ca2+]i is controlled by the balance between Ca entry and efflux during systole. Furthermore, manoeuvres which decrease the amplitude of the Ca transient (without decreasing Ca influx) will therefore increase diastolic [Ca2+]i. This identifies a novel mechanism whereby changes of the amplitude of the systolic Ca transient control diastolic [Ca2+]i.

Increased Ca buffering underpins remodelling of Ca2+ handling in old sheep atrial myocytes.

Abstract: Key points Ageing is associated with an increased risk of cardiovascular disease and arrhythmias, with the most common arrhythmia being found in the atria of the heart. Little is known about how the normal atria of the heart remodel with age and thus why dysfunction might occur. We report alterations to the atrial systolic Ca2+ transient that have implications for the function of the atrial in the elderly. We describe a novel mechanism by which increased Ca buffering can account for changes to systolic Ca2+ in the old atria. The present study helps us to understand how the processes regulating atrial contraction are remodelled during ageing and provides a basis for future work aiming to understand why dysfunction develops. Abstract Many cardiovascular diseases, including those affecting the atria, are associated with advancing age. Arrhythmias, including those in the atria, can arise as a result of electrical remodelling or alterations in Ca2+ homeostasis. In the atria, age-associated changes in the action potential have been documented. However, little is known about remodelling of intracellular Ca2+ homeostasis in the healthy aged atria. Using single atrial myocytes from young and old Welsh Mountain sheep, we show the free Ca2+ transient amplitude and rate of decay of systolic Ca2+ decrease with age, whereas sarcoplasmic reticulum (SR) Ca content increases. An increase in intracellular Ca buffering explains both the decrease in Ca2+ transient amplitude and decay kinetics in the absence of any change in sarcoendoplasmic reticulum calcium transport ATPase function. Ageing maintained the integrated Ca2+ influx via ICa-L but decreased peak ICa-L. Decreased peak ICa-L was found to be responsible for the age-associated increase in SR Ca content but not the decrease in Ca2+ transient amplitude. Instead, decreased peak ICa-L offsets increased SR load such that Ca2+ release from the SR was maintained during ageing. The results of the present study highlight a novel mechanism by which increased Ca buffering decreases systolic Ca2+ in old atria. Furthermore, for the first time, we have shown that SR Ca content is increased in old atrial myocytes.

198 Heart failure increases mitochondrial s-nitrosylation

Abstract: Heart failure affects over 5 50 000 people living in the United Kingdom (1) and roughly half of those present with reduced cardiac ejection fraction (2). The electron transport chain (ETC) within the mitochondria is the principle source of ATP within cardiac muscle. Consequently, the regulation of the ETC in heart failure represents a potential rate limiting step to cardiac contraction in the disease state. The post-translational modification of proteins by nitric oxide, S-nitrosylation (S-NO) has previously been shown to have inhibitor effects on complex I activity (3). The aim of this study is therefore to investigate the role of S-NO and how this may regulate ETC activity in an ovine tachypaced model of heart failure. Tachypacing induced heart failure resulted in an increase in left ventricular diameter (3.100.06cm to 4.040.13cm, p This study demonstrates that in heart failure there is a gross increase in the level of myocardial S-NO. Within the mitochondria, S-NO of electron transport chain proteins is also increased, having an inhibitory effect on ATP production. This work therefore provides a novel insight into how S-NO may contribute to the deterioration of cardiac contractile function in heart failure. References . Townsend NWJ, Bhatnagar P, Wickramasinghe K, Rayner M. Cardiovascular disease statistics 2014. London: British Heart Foundation; 2014. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. Executive Summary: Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation. 2016;133(4):447-54. Epub 2016/01/27. . Chouchani ET, Methner C, Nadtochiy SM, Logan A, Pell VR, Ding SJ, et al. Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I. Nat Med. 2013;19(6):753.