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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cardiac ryanodine receptor has become a subject of increasing interest as its role in the etiology of cardiac disease is becoming more apparent. In this article, we review the current knowledge of the structure and function of the cardiac ryanodine receptor and its implications in cardiac pathophysiology. Cardiac ryanodine receptors function by regulating calcium release from the sarcoplasmic reticulum in cardiomyocytes, thereby playing an integral role in excitation-contraction coupling. In heart failure, the myocardium remains in a chronic hyperadrenergic state. This leads to protein kinase A hyperphosphorylation of ryanodine receptors within cardiomyocytes, ultimately leading to calcium leakage from the sarcoplasmic reticulum into the cytosol and thus impairing excitation-contraction coupling. These mechanisms could partially explain the pathophysiology underlying the reduced cardiac output seen in heart failure. Beta-adrenergic blockade appears to correct the abnormality and reestablishes normal ryanodine receptor function. These calcium leaks can also generate delayed afterdepolarizations, which can lead to fatal arrhythmias. Two genetic diseases have been linked to mutations in the cardiac ryanodine receptor: arrhythmogenic right ventricular dysplasia type 2 and catecholaminergic polymorphic ventricular tachycardia or familial polymorphic ventricular tachycardia. As our understanding of this receptor and its modulators deepens, the possibility of clinical application draws near.
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PMID:The cardiac ryanodine receptor (RyR2) and its role in heart disease. 1583 Nov 48

Heart failure leading to ventricular arrhythmogenesis is a major cause of clinical mortality and has been associated with a leak of sarcoplasmic reticular Ca(2+) into the cytosol due to increased open probabilities in cardiac ryanodine receptor Ca(2+)-release channels. Caffeine similarly increases such open probabilities, and so we explored its arrhythmogenic effects on intact murine hearts. A clinically established programmed electrical stimulation protocol adapted for studies of isolated intact mouse hearts demonstrated that caffeine (1 mM) increased the frequency of ventricular tachycardia from 0 to 100% yet left electrogram duration and latency unchanged during programmed electrical stimulation, thereby excluding slowed conduction as a cause of arrhythmogenesis. We then used fluorescence measurements of intracellular Ca(2+) concentration in isolated mouse ventricular cells to investigate parallel changes in Ca(2+) homeostasis associated with these arrhythmias. Both caffeine (1 mM) and FK506 (30 microM) reduced electrically evoked cytosolic Ca(2+) transients yet increased the frequency of spontaneous Ca(2+)-release events. Diltiazem (1 microM) but not nifedipine (1 microM) pretreatment suppressed these increases in frequency. Identical concentrations of diltiazem but not nifedipine correspondingly suppressed the arrhythmogenic effects of caffeine in whole hearts. These findings thus directly implicate spontaneous Ca(2+) waves in triggered arrhythmogenesis in intact hearts.
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PMID:Caffeine-induced arrhythmias in murine hearts parallel changes in cellular Ca(2+) homeostasis. 1592 7

The abnormally regulated release of Ca2+ from an intracellular Ca2+ store, the sarcoplasmic reticulum (SR), is the mechanism underlying contractile and relaxation dysfunctions in heart failure (HF). According to recent reports, protein kinase A (PKA)-mediated hyperphosphorylation of ryanodine receptor (RyR) in the SR has been shown to cause the dissociation of FK506 binding protein (FKBP) 12.6 from the RyR in heart failure. This causes an abnormal Ca2+ leak through the Ca2+ channel located in the RyR, leading to an increase in the cytosolic Ca2+ during diastole, prolongation of the Ca2+ transient, and delayed/slowed diastolic Ca2+ re-uptake. More recently, a considerable number of disease-linked mutations in the RyR have been reported in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) or arrhythmogenic right ventricular dysplasia type 2. An analysis of the disposition of these mutation sites within well-defined domains of the RyR polypeptide chain has led to the new concept that interdomain interactions among these domains play a critical role in channel regulation, and an altered domain interaction causes channel dysfunction in the failing heart. The knowledge gained from the recent literature concerning the critical proteins and the changes in their properties under pathological conditions has brought us to a better position to develop new pharmacological or genetic strategies for the treatment of heart failure or cardiac arrhythmia. A considerable body of evidence reviewed here indicates that abnormal RyR function plays an important role in the pathogenesis of heart failure. This review also covers some controversial issues in the literature concerning the involvement of phosphorylation and FKBP12.6.
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PMID:Abnormal ryanodine receptor function in heart failure. 1595 Oct 21

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterised by progressive fibro-fatty replacement of right ventricular myocardium. Earlier studies described ARVC as non-inflammatory, non-coronary disorder associated with arrhythmias, heart failure and sudden death due to functional exclusion of the right ventricle. Molecular genetic studies have identified nine different loci associated with ARVC; accordingly each locus is implicated for each type of ARVC (ARVC1-ARVC9). So far five genes have been identified as containing pathogenic mutations for ARVC. Though mutations in each of the gene/s indicate disruption of different pathways leading to the condition, the exact pathogenesis of the condition is still obscure. This review tries to understand the pathogenesis of the condition by examining the individual proteins implicated and relate them to the pathways that could play a role in the aetiology of the condition. Cardiac ryanodine receptor (RYR-2), which regulates intra-cellular Ca(2+) concentration by releasing Ca(2+) reserves from the sarcoplasmic reticulum (SR), was the first gene for ARVC. The mutation in this gene is believed to disrupt coupled gating of RYR-2, causing after-depolarisation, leading to arrhythmias followed by structural changes due to altered intra-cellular Ca(2+) levels. Three other genes implicated for ARVC, plakoglobin (Naxos disease), desmoplakin (ARVC8) and plakophilin (ARVC9) have prompted the speculation that ARVC is primarily a disease of desmosomes. But identification of TGFbeta-3 for ARVC1 and the role of all these three genes (plakoglobin, desmoplakin and plakophilin) in cardiac morphogenesis indicate some kind of signal-transducing pathway disruption in the condition. The finding that ARVC as a milder form of Uhl's anomaly indicates similar ontogeny for the condition. Further, discovery of apoptotic cells in the autopsy of the right ventricular myocardium of ARVC patients does indicate a common pathway for different types of ARVCs, which is more specific for the right ventricular myocardium involving desmosomal plaque proteins, growth factors and Ca(2+) receptors.
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PMID:Etiopathogenesis of arrhythmogenic right ventricular cardiomyopathy. 1609 17

During calcium-induced calcium-release, the ryanodine receptor (RyR) opens and releases large amounts of calcium from the sarcoplasmic reticulum into the cytoplasm of the myocyte. Recent experiments have suggested that cooperativity between the four monomers comprising the RyR plays an important role in the dynamics of the overall receptor. Furthermore, this cooperativity can be affected by the binding of FK506 binding protein, and hence, modulated by adrenergic stimulation through the phosphorylating action of protein kinase A. This has important implications for heart failure, where it has been hypothesized that RyR hyperphosphorylation, resulting in a loss of cooperativity, can lead to a persistent leak and a reduced sarcoplasmic-reticula content. In this study, we construct a theoretical model that examines the cooperativity via the assumption of an allosteric interaction between the four subunits. We find that the level of cooperativity, regulated by the binding of FK506 binding-protein, can have a dramatic effect on the excitation-contraction coupling gain and that this gain exhibits a clear maximum. These findings are compared to currently available data from different species and allows for an evaluation of the aforementioned heart-failure scenario.
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PMID:Excitation-contraction coupling gain and cooperativity of the cardiac ryanodine receptor: a modeling approach. 1612 27

Most of the calcium that activates contraction in the heart comes from the sarcoplasmic reticulum (SR) and it is therefore essential to control the SR Ca content. SR Ca content reflects the balance between uptake (via the SR Ca-ATPase, SERCA) and release, largely via the ryanodine receptor (RyR). Unwanted changes of SR Ca are prevented because, for example, an increase of SR Ca content increases the amplitude of the systolic Ca transient and this, in turn, results in increased loss of Ca from and decreased Ca entry into the cell thereby restoring cell and SR Ca towards control levels. We discuss the parameters that affect the steady level of SR Ca and how these may change in heart failure. Finally, we discuss disordered Ca regulation with particular emphasis on the condition of alternans where successive heartbeats alternate in amplitude. This behaviour can be explained by excessive feedback gain in the processes controlling SR Ca.
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PMID:The control of sarcoplasmic reticulum Ca content in cardiac muscle. 1613 53

Cardiac excitation-contraction coupling is initialized by the release of Ca from the sarcoplasmic reticulum (SR) in response to a sudden increase in local cytosolic [Ca] ([Ca]i) within the junctional cleft. We have tested the hypothesis that functional ryanodine receptor (RyR) regulation plays a major role in the regulation of myocyte Ca. A mathematical model with unique characteristics was used to simulate Ca homeostasis. Specifically, the model was designed to accurately represent the SR [Ca]-dependence of release from a variety of experimentally produced data sets. The simulated data for altered RyR Ca sensitivity demonstrated a regulatory feedback loop that resulted in the same release at lower [Ca]SR. This suggests that the primary role of myocyte RyR regulation may be to decrease SR [Ca] without decreasing the size of the [Ca]i transient. The model results suggest that this action moderates the increased SR [Ca] observed with adrenergic stimulation and may keep the [Ca]SR below the threshold for delayed afterdepolarizations and arrhythmia. However, increased Ca affinity of the RyR increased the probability of delayed afterdepolarizations when heart failure was simulated. We conclude that RyR regulation may play a role in preventing arrhythmias in healthy myocytes but that the same regulation may have the opposite effect in chronic heart failure.
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PMID:Regulation of cardiac sarcoplasmic reticulum Ca release by luminal [Ca] and altered gating assessed with a mathematical model. 1616 70

Diminished Ca release from the sarcoplasmic reticulum (SR) is an important contributor to the impaired contractility of the failing heart. Despite extensive effort, the underlying causes of abnormal SR Ca release in heart failure (HF) remain unknown. We used a combination of simultaneous imaging of cytosolic and SR intraluminal [Ca] in isolated cardiomyocytes and recordings from single-ryanodine receptor (RyR) channels reconstituted into lipid bilayers to investigate alterations in intracellular Ca handling in an experimental model of chronic HF. We found that diastolic free [Ca] inside the SR was dramatically reduced because of a Ca leak across the SR membrane, mediated by spontaneous local release events (Ca sparks), in HF myocytes. Additionally, the magnitudes of intrastore Ca depletion signals during global and focal Ca release events were blunted, and [Ca]SR recovery was slowed after global but not focal Ca release in HF myocytes. At the single-RyR level, the sensitivity of RyRs to activation by luminal Ca was greatly enhanced, providing a molecular mechanism for the maintained potentiation of Ca sparks (and increased Ca leak) at reduced intra-SR [Ca] in HF. This work shows that the diminished SR Ca release characteristic of failing myocardium could be explained by increased sensitivity of RyRs to luminal Ca, leading to enhanced spark-mediated SR Ca leak and reduced intra-SR [Ca].
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PMID:Abnormal intrastore calcium signaling in chronic heart failure. 1617 92

Calstablin2 stabilises the ryanodine receptor (RyR2), preventing aberrant activation of the channels during the resting phase of the cardiac muscle. Loss of this stabilisation may be associated with cardiac arrhythmias, the sudden death occasionally observed in people with structurally normal hearts, as well as the atrial fibrillation in heart failure. Calstabin2-deficient mice have structurally normal hearts but exhibit exercise-induced cardiac ventricular arrhythmias that cause sudden death. In arrhythmias, the calstabin2 stabiliser JTV519 did not prevent arrhythmias in calstabin2-/- mice, but reduced the arrhythmias in calstabin2+/- mice, illustrating the antiarrhythmic potential of stabilising calstablin2. Familial polymorphic ventricular tachycardia in humans has been linked to missense mutants in the hRyR2 gene. In HEK293 cells, these RyR2 mutants showed less binding of 35S-calstabin2 than the wild type, indicating a reduced binding affinity. In human atrial fibrillation and heart failure, where there is excessive disassociation of calstabin2 from the RyR2 receptor in vitro, JTV519 is able to reverse this. In conclusion, calstabin2 is an important new target in sudden cardiac death associated with structurally normal hearts, and in the treatment of atrial fibrillation and heart failure.
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PMID:Stabilisation of calstabin2--a new approach in sudden cardiac death. 1618 51

Phosphodiesterases (PDEs) regulate the local concentration of 3',5' cyclic adenosine monophosphate (cAMP) within cells. cAMP activates the cAMP-dependent protein kinase (PKA). In patients, PDE inhibitors have been linked to heart failure and cardiac arrhythmias, although the mechanisms are not understood. We show that PDE4D gene inactivation in mice results in a progressive cardiomyopathy, accelerated heart failure after myocardial infarction, and cardiac arrhythmias. The phosphodiesterase 4D3 (PDE4D3) was found in the cardiac ryanodine receptor (RyR2)/calcium-release-channel complex (required for excitation-contraction [EC] coupling in heart muscle). PDE4D3 levels in the RyR2 complex were reduced in failing human hearts, contributing to PKA-hyperphosphorylated, "leaky" RyR2 channels that promote cardiac dysfunction and arrhythmias. Cardiac arrhythmias and dysfunction associated with PDE4 inhibition or deficiency were suppressed in mice harboring RyR2 that cannot be PKA phosphorylated. These data suggest that reduced PDE4D activity causes defective RyR2-channel function associated with heart failure and arrhythmias.
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PMID:Phosphodiesterase 4D deficiency in the ryanodine-receptor complex promotes heart failure and arrhythmias. 1621 10


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