Rajiv Sankaranarayanan

Biphasic decay of the Ca transient results from increased sarcoplasmic reticulum Ca leak

Ca leak from the sarcoplasmic reticulum through the ryanodine receptor (RyR) reduces the amplitude of the Ca transient and slows its rate of decay. In the presence of β‐adrenergic stimulation, RyR‐mediated Ca leak produces a biphasic decay of the Ca transient with a fast early phase and a slow late phase. Two forms of Ca leak have been studied, Ca‐sensitising (induced by caffeine) and non‐sensitising (induced by ryanodine) and both induce biphasic decay of the Ca transient. Only Ca‐sensitising leak can be reversed by traditional RyR inhibitors such as tetracaine. Ca leak can also induce Ca waves. At low levels of leak, waves occur. As leak is increased, first biphasic decay and then slowed monophasic decay is seen. The level of leak has major effects on the shape of the Ca transient.

Are the anti-arrhythmic effects of omega-3 fatty acids due to modulation of myocardial calcium handling?

Both animal and clinical studies have demonstrated that omega-3 fatty acids have anti-arrhythmic properties. It has been suggested that these anti-arrhythmic effects are due to modulation of the activity of various myocardial calcium handling proteins such as ryanodine receptor (RyR), L-type calcium current and sodium/calcium exchanger. In this article, we review all the data available on the effects of omega-3 fatty acids on ventricular myocardial calcium handling. In addition we highlight some unanswered questions and discuss possible therapeutic benefits of omega-3 fatty acids.

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

For the heart to function as a pump, intracellular calcium concentration ([Ca2+]i) must increase during systole to activate contraction and then fall, during diastole, to allow the myofilaments to relax and the heart to refill with blood. The present study investigates the control of diastolic [Ca2+]i in rat ventricular myocytes. We show that diastolic [Ca2+]i is increased by manoeuvres that decrease sarcoplasmic reticulum function. This is accompanied by a decrease of systolic [Ca2+]i such that the time‐averaged [Ca2+]i remains constant. We report that diastolic [Ca2+]i is controlled by the balance between Ca2+ entry and Ca2+ efflux during systole. The results of the present study identify a novel mechanism by which changes of the amplitude of the systolic Ca transient control diastolic [Ca2+]i.

The effect of 2,5-di-(tert-butyl)-1,4-benzohydroquinone (TBQ) on intracellular Ca2+ handling in rat ventricular myocytes.

Graphical abstract

A Tale of Two Leaks

Over the last 2 decades, understanding of the mechanisms that underlie heart failure (HF) has grown enormously. One of the key concepts is that HF is associated with profound alterations in myocardial calcium handling and excitation-contraction coupling. Article see p 970 Most of the calcium that activates contraction comes from the sarcoplasmic reticulum (SR). It leaves the SR through a specialized release channel known as the ryanodine receptor (RyR). The probability that an RyR is open and can therefore allow Ca to leave the SR into the cytoplasm is increased by an increase in the concentration of either cytosolic or SR (luminal) Ca concentration. During the normal heartbeat, sarcolemmal Ca channels open and some of the entering Ca binds to the RyRs, making them open, thereby triggering the release of a much greater amount of Ca from the SR into the cytosol. This Ca release causes a rapid rise of cytosolic Ca to levels that activate the myofilaments and initiate contraction. After termination of release of Ca from the SR (because of closure of RyRs), cytosolic Ca levels decline rapidly and relaxation occurs. Ca is rapidly removed from the cytosol by 2 major systems: the sarcoendoplasmic reticulum Ca ATPase and the sarcolemmal sodium/calcium exchanger. Sarcoendoplasmic reticulum Ca ATPase pumps Ca back into the SR, whereas sarcolemmal sodium/calcium exchanger pumps 1 Ca2+ out in exchange for the influx of 3 Na+ ions into the cell. This rapid cycle of Ca release and reuptake is known as the systolic Ca transient, and it is one of the main factors that control force of contraction in the heart. It is worth emphasizing that the normal Ca transient depends on the RyRs being virtually closed in diastole, opening very briefly to produce the systolic increase of Ca, and then closing to allow …

Are Some Anticoagulants More Equal Than Others? - Evaluating the Role of Novel Oral Anticoagulants in AF Ablation

Left atrial ablation strategies are being increasingly performed as a Class 1 therapeutic indication for drug refractory paroxysmal atrial fibrillation (AF). Traditionally AF ablation has been performed with patients on uninterrupted warfarin therapy, however over the last few years, novel oral anticoagulants (NOACs) have emerged as attractive alternatives to warfarin in order to reduce stroke risk due to AF. NOACs are therefore increasingly being used instead of warfarin in the management of AF. There is also mounting evidence mainly in the form of small randomised studies and meta-analysis that have demonstrated that the use of NOACs for AF ablation is efficacious, safe and convenient. However the peri-procedural dosing protocols used in various studies especially in terms of whether NOAC use is interrupted or uninterrupted during AF ablation, have significant inter-operator and inter-institution variability. Currently there is also a lack of randomised controlled trials to validate the data obtained from meta-analyses. There is also evidence that use of NOACs may increase the requirement of unfractionated heparin during the procedure. This review article shall examine the currently available evidence-base, appraise the gaps in the current evidence and also underscore the need for larger randomised clinical trials in this rapidly developing field.

Effect of reduction in ryanodine receptor calcium leak on arrhythmogenesis in rat ventricular myocytes

Abstract Background Cardiomyocytes in heart failure have increased ryanodine receptor (RyR) open probability (po) leading to calcium leak from the sarcoplasmic reticulum. This process results in calcium waves, delayed after-depolarisations, and subsequent ventricular arrhythmias. However, this leak will decrease the calcium content of the sarcoplasmic reticulum which will in turn decrease the occurrence of waves. We therefore hypothesised that with extreme RyR leak (such as in end-stage heart failure) the calcium content of the sarcoplasmic reticulum might be too low to sustain calcium waves and that part correction of severe leak could lead to a resurgence of calcium waves. Methods We used single rat ventricular myocytes, voltage clamped using the perforated patch clamp technique. Cells were stimulated at 0·5 Hz with 100 ms duration depolarising pulses from −40 to 0 mV. Cytosolic calcium concentration was measured with the Fluo-4 AM indicator. Calcium waves were induced by the application of 1 μmol/L isoproterenol in raised external calcium concentration (2 or 3 mM). Severe RyR leak was induced with caffeine (1–2 mM), and then tetracaine (50–100 μM) was co-applied to reduce RyR po. Findings Isoproterenol increased the amplitude of the systolic calcium transient in all the myocytes studied and induced calcium waves in 26 (87%) of 30 myocytes. Application of 1 mM caffeine abolished calcium waves in 11 (65%) of 17 of these myocytes and reduced the frequency of waves in the remaining six cells. Application of 2 mM caffeine abolished calcium waves in all nine myocytes. Subsequent addition of tetracaine (50 μM) led to a re-emergence or increased frequency of waves in nine (53%) of 17 myocytes whereas 100 μM tetracaine re-established calcium waves in 14 (93%) of 15 myocytes (50 vs 100 μM tetracaine, Fishers exact test p=0·02). Interpretation Induction of severe calcium leak depleted the calcium content of the sarcoplasmic reticulum below the level required for calcium waves. Inhibition of RyR leak could be a useful therapeutic strategy in heart failure to improve systolic contraction as well as relaxation. However, this strategy might also be pro-arrhythmogenic since part correction of leak can replenish the calcium content of the sarcoplasmic reticulum above the level required for initiation of calcium waves. Funding British Heart Foundation.