Increasing Ryanodine Receptor Open Probability Alone Does Not Produce Arrhythmogenic Calcium Waves

Venetucci, Luigi; Trafford, Andrew W.; Eisner, David

doi:10.1161/01.res.0000252828.17939.00

Cited by 179 publications

(166 citation statements)

References 44 publications

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“…Consistent with previous reports, cell capacitance was significantly lower in atrophic than in control cardiac myocytes (123±3 pF, n=96 vs. 161±5 pF, n=98, p<0.0001) [40]. At a holding potential of V Pip =−90 mV, Ca 2+ release from the SR was induced by rapid superperfusion of the investigated cardiac myocyte with 10 mmol/l caffeine [30,38,49,50,54]. In the presence of caffeine, Ca 2+ is released from the SR, cannot be stored in the SR again and is therefore completely removed from the cytoplasm by the Na + -Ca 2+ exchanger [8,27].…”

Section: Sr Ca 2+ Contentsupporting

confidence: 91%

Enhanced Ca2+ influx through cardiac L-type Ca2+ channels maintains the systolic Ca2+ transient in early cardiac atrophy induced by mechanical unloading

Biermann¹,

Bernhardt²,

Neef³

et al. 2014

Thorac cardiovasc Surg

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Cardiac atrophy as a consequence of mechanical unloading develops following exposure to microgravity or prolonged bed rest. It also plays a central role in the reverse remodelling induced by left ventricular unloading in patients with heart failure. Surprisingly, the intracellular Ca 2+ transients which are pivotal to electromechanical coupling and to cardiac plasticity were repeatedly found to remain unaffected in early cardiac atrophy. To elucidate the mechanisms underlying the preservation of the Ca 2+ transients, we investigated Ca 2+ cycling in cardiomyocytes from mechanically unloaded (heterotopic abdominal heart transplantation) and control (orthotopic) hearts in syngeneic Lewis rats. Following 2 weeks of unloading, sarcoplasmic reticulum (SR) Ca 2+ content was reduced by~55 %. Atrophic cardiac myocytes also showed a much lower frequency of spontaneous diastolic Ca 2+ sparks and a diminished systolic Ca 2+ release, even though the expression of ryanodine receptors was increased by~30 %. In contrast, current clamp recordings revealed prolonged action potentials in endocardial as well as epicardial myocytes which were associated with a two to fourfold higher sarcolemmal Ca 2+ influx under action potential clamp. In addition, Cav1.2 subunits which form the pore of L-type

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Section: Sr Ca 2+ Contentsupporting

confidence: 91%

Enhanced Ca2+ influx through cardiac L-type Ca2+ channels maintains the systolic Ca2+ transient in early cardiac atrophy induced by mechanical unloading

Biermann¹,

Bernhardt²,

Neef³

et al. 2014

Thorac cardiovasc Surg

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“…Another stimulus is, therefore, needed to keep sarcoplasmic reticulum Ca 2+ content at a level sufficient for Ca 2+ wave production. 47 We believe that in ADHF, continued βAR stimulation activates CaMKII, causing diastolic Ca 2+ leak from the sarcoplasmic reticulum via ryanodine receptor phosphorylation, and that PKA activation maintains sarcoplasmic reticulum Ca 2+ at a level sufficiently high for the production of arrhythmogenic Ca 2+ waves. In addition to alterations in Ca 2+ handling, CaMKII can also phosphorylate ion channels.…”

Section: Calcium/calmodulin-dependent Protein Kinase IImentioning

confidence: 98%

Mechanisms of Disease: detrimental adrenergic signaling in acute decompensated heart failure

et al. 2008

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SUMMARYAcute decompensated heart failure (ADHF) is responsible for more than 1 million hospital admissions each year in the US. Clinicians and scientists have developed therapeutic strategies that reduce mortality in patients with chronic heart failure (HF). Despite the widely appreciated magnitude of the ADHF problem, there is still a critical gap in our understanding of the cellular mechanisms involved and effective treatment strategies for hospitalized patients. Irrespective of the etiology, patients with ADHF present with similar symptoms (e.g. edema, altered hemodynamics and congestion) as multiple signaling pathways converge in a common phenotypic presentation. Investigations have shown that patients with ADHF have increased catecholamine levels, which cause chronic stimulation of β-adrenergic receptors. This overstimulation leads to chronic G-protein activation and perturbations in myocyte signaling, as the patient's heart attempts to adapt to progressive HF. Over time, these compensatory signaling mechanisms ultimately fail, and maladaptive signaling prevails with progressive worsening of symptoms. This Review summarizes some of the changes that occur during chronic adrenergic stimulation, and examines how downstream contractile dysfunction and myocyte death can alter the prognosis of patients with HF hospitalized for acute events.

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“…14 This increased opening will lead to a diastolic leak of Ca, thereby decreasing the SR Ca content. In addition to decreasing systolic function, the leak may also interfere with relaxation by opposing Ca reuptake into the SR. 15 The relative importance of decreased SERCA activity as opposed to increased NCX and RyR leak may depend on the exact model used. For example, in a canine model of heart failure induced by rapid pacing, 16 it was found that the bulk of the problems of Ca handling could be attributed to increased leak, whereas in a rabbit model, aortic insufficiency and stenosis changes of NCX were most important.…”

Section: Sr Function In Heart Failurementioning

confidence: 99%

Sarcoplasmic Reticulum Ca-ATPase and Heart Failure 20 Years Later

Eisner

Caldwell

Trafford

2013

Circulation Research

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T his article reflects on the impact of a classic paper identifying the effects of loss of sarcoplasmic reticulum Ca-ATPase activity in heart failure. The Classic ArticleUnderstanding the effects of heart failure on contraction and Ca signaling in the heart has long been a priority. By the late 1980s, many studies on animal models had shown that heart failure resulted in a slowing of the decay of the systolic Ca transient 1 because of a decrease in the expression of the sarcoplasmic reticulum (SR) Ca-ATPase (SERCA).2 Work using human tissue found similar changes.3,4 In 1994, Hasenfuss et al 5 published a now classic article in Circulation Research entitled "Relation between myocardial function and expression of sarcoplasmic reticulum Ca-ATPase in failing and non-failing human myocardium." Previous work had shown that SERCA expression and activity were decreased in heart failure. Other work had shown that the increase of force seen on increasing the frequency of stimulation (the positive forcefrequency curve) disappeared in heart failure. Hasenfuss et al 5 showed that the degree of change in the force-frequency relationship correlated with the loss of SERCA. Hearts with low levels of SERCA developed maximum force at lower frequencies than those with higher levels. In addition, and suggested as causative of the reduced force-frequency responses, the failing hearts had reduced SERCA-mediated Ca uptake.The work in this article has influenced 2 areas of research: changes of SR function in heart failure and restoration of SERCA as a therapeutic strategy. We consider these in turn. SR Function in Heart FailureTwenty years later, the role of changes of SERCA expression in heart failure is well-established. The majority of studies of heart failure in either humans or experimental animals show that SERCA activity is decreased in heart failure. This decrease of SERCA has 2 immediate effects on Ca signaling. First, it slows the rate of decay of the systolic Ca transient, thereby impairing relaxation. Second, as a consequence of decreasing SR Ca content, it will decrease the amplitude of the systolic Ca transient and thus contraction. However, subsequent work has shown that changes of SERCA are part of a group of changes of Ca signaling that occur in heart failure. As highlighted in Figure, 2 other factors will also decrease the SR Ca content. First, there is an increase of NCX expression or activity. [6][7][8] This adaptation has the benefit of making up for the reduced SERCA, thereby preserving relaxation. In a subsequent article, Hasenfuss et al 9 showed that patients with increased NCX had better diastolic function than did those with lower NCX. However, although increased NCX improves diastolic function, it will decrease SR Ca content and thereby depress systolic function further. Second, many studies have now shown that the open probability of the RyR is increased in heart failure. [10][11][12] This may occur as a result of phosphorylation, 10 hyponitrosylation, 13 or oxidation. 14 This increased opening will lead to a...

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Increasing Ryanodine Receptor Open Probability Alone Does Not Produce Arrhythmogenic Calcium Waves

Cited by 179 publications

References 44 publications

Enhanced Ca2+ influx through cardiac L-type Ca2+ channels maintains the systolic Ca2+ transient in early cardiac atrophy induced by mechanical unloading

Enhanced Ca2+ influx through cardiac L-type Ca2+ channels maintains the systolic Ca2+ transient in early cardiac atrophy induced by mechanical unloading

Mechanisms of Disease: detrimental adrenergic signaling in acute decompensated heart failure

Sarcoplasmic Reticulum Ca-ATPase and Heart Failure 20 Years Later

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