UMLS:C0018801 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

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

The cardiac ryanodine receptor (RyR2), the major calcium release channel on the sarcoplasmic reticulum (SR) in cardiomyocytes, has recently been shown to be involved in at least two forms of sudden cardiac death (SCD): (1) Catecholaminergic polymorphic ventricular tachycardia (CPVT) or familial polymorphic VT (FPVT); and (2) Arrhythmogenic right ventricular dysplasia type 2 (ARVD2). Eleven RyR2 missense mutations have been linked to these diseases. All eleven RyR2 mutations cluster into 3 regions of RyR2 that are homologous to the three malignant hyperthermia (MH)/central core disease (CCD) mutation regions of the skeletal muscle ryanodine receptor/calcium release channel RyR1. MH/CCD RyR1 mutations have been shown to alter calcium-induced calcium release. Sympathetic nervous system stimulation leads to phosphorylation of RyR2 by protein kinase A (PKA). PKA phosphorylation of RyR2 activates the channel. In conditions associated with high rates of SCD such as heart failure RyR2 is PKA hyperphosphorylated resulting in "leaky" channels. SR calcium leak during diastole can generate "delayed after depolarizations" that can trigger fatal cardiac arrhythmias (e.g., VT). We propose that RyR2 mutations linked to genetic forms of catecholaminergic-induced SCD may alter the regulation of the channel resulting in increased SR calcium leak during sympathetic stimulation.
...
PMID:Involvement of the cardiac ryanodine receptor/calcium release channel in catecholaminergic polymorphic ventricular tachycardia. 1180 5

Cardiac excitation-contraction coupling occurs by a calcium ion-mediated mechanism in which the signal of action potential is converted into Ca2+ influx into the cardiomyocytes through the sarcolemmal L-type calcium channels. This is followed by Ca2+-induced release of additional Ca2+ ions from the lumen of the sarcoplasmic reticulum into the cytosol via type 2 ryanodine receptors (RyR2). RyR2 channels form large complexes with additional regulatory proteins, including FKBP12.6 and calsequestrin 2 (CASQ2). Catecholamines, released into the body fluids during emotional or physical stress, activate Ca2+-induced Ca2+ release by protein kinase A-mediated phosphorylation of RyR2. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an insidious, early-onset and highly malignant, inherited disorder characterized by effort-induced ventricular arrhythmias in the absence of structural alterations of the heart. At least some cases of sudden, unexplained death in young individuals may be ascribed to CPVT. Mutations of the RyR2 gene cause autosomal dominant CPVT, while mutations of the CASQ2 gene may cause an autosomal recessive or dominant form of CPVT. The steps of the molecular pathogenesis of CPVT are not entirely clear, but inappropriate "leakiness" of RyR2 channels is thought to play a role; the underlying mechanisms may involve an increase in the basal activity of the RyR2 channel, alterations in its phosphorylation status, a defective interaction of RyR2 with other molecules or ions, such as FKBP12.6, CASQ2, or Mg2+, or its abnormal activation by extra- or intraluminal Ca2+ ions. Beta-adrenergic antagonists have proven to be of value in prevention of arrhythmias in CPVT patients, but occasional treatment failures call for alternative measures. There is great interest at present for the development of novel antiarrhythmic drugs for CPVT, as the same approaches may be applied for treatment of more common forms of life-threatening arrhythmias, such as those arising during ischemia and heart failure.
...
PMID:Catecholaminergic polymorphic ventricular tachycardia: recent mechanistic insights. 1591 75

The RyR (ryanodine receptor) mediates rapid Ca2+ efflux from the ER (endoplasmic reticulum) and is responsible for triggering numerous Ca2+-activated physiological processes. The most studied RyR-mediated process is excitation-contraction coupling in striated muscle, where plasma membrane excitation is transmitted to the cell interior and results in Ca2+ efflux that triggers myocyte contraction. Recently, single-residue mutations in the cardiac RyR (RyR2) have been identified in families that exhibit CPVT (catecholaminergic polymorphic ventricular tachycardia), a condition in which physical or emotional stress can trigger severe tachyarrhythmias that can lead to sudden cardiac death. The RyR2 mutations in CPVT are clustered in the N- and C-terminal domains, as well as in a central domain. Further, a critical signalling role for dysfunctional RyR2 has also been implicated in the generation of arrhythmias in the common condition of HF (heart failure). We have prepared cardiac RyR2 plasmids with various CPVT mutations to enable expression and analysis of Ca2+ release mediated by the wild-type and mutated RyR2. These studies suggest that the mutational locus may be important in the mechanism of Ca2+ channel dysfunction. Understanding the causes of aberrant Ca2+ release via RyR2 may assist in the development of effective treatments for the ventricular arrhythmias that often leads to sudden death in HF and in CPVT.
...
PMID:Role of ryanodine receptor mutations in cardiac pathology: more questions than answers? 1705 26

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a malignant arrhythmia syndrome linked to mutations in the cardiac ryanodine receptor (RyR2) and calsequestrin (CASQ2). RyR2 and CASQ2 are parts of the multimolecular Ca(2+) release channel complex that is present on the sarcoplasmic reticulum (SR) to support myocyte Ca(2+) cycling and contractile activity. Whereas RyR2 operates as a Ca(2+) release channel, the SR Ca(2+) binding protein CASQ2 plays a dual role by serving as a SR Ca(2+) buffer and by regulating RyR2 function. Essential to stable Ca(2+) cycling, SR luminal Ca(2+)-dependent control of RyR2 activity by CASQ2 contributes to RyR2 deactivation and to the development of a temporary refractory state that occurs after each Ca(2+) release. Accumulating evidence suggests that the CPVT mutations act by reducing the extent and shortening the duration of Ca(2+) signaling refractoriness, thereby promoting untimely SR Ca(2+) release and arrhythmogenic delayed afterdepolarizations in cardiac myocytes. Similar mechanisms may apply to arrhythmias during various conditions, including heart failure and ischemic heart disease, associated with acquired defects in components of the Ca(2+) release channel complex.
...
PMID:Molecular basis of catecholaminergic polymorphic ventricular tachycardia. 1912 13

Channelopathies, caused by disturbed potassium or calcium ion management in cardiac myocytes are a major cause of heart failure and sudden cardiac death worldwide. The human ryanodine receptor 2 (RYR2) is one of the key players tightly regulating calcium efflux from the sarcoplasmic reticulum to the cytosol and found frequently mutated (<60%) in context of catecholaminergic polymorphic ventricular tachycardia (CPVT1). We tested 35 Kazakhstani patients with episodes of ventricular arrhythmia, two of those with classical CPVT characteristics and 33 patients with monomorphic idiopathic ventricular arrhythmia, for variants in the hot-spot regions of the RYR2 gene. This approach revealed two novel variants; one de-novo RYR2 mutation (c13892A>T; p.D4631V) in a CPVT patient and a novel rare variant (c5428G>C; p.V1810L) of uncertain significance in a patient with VT of idiopathic origin which we suggest represents a low-penetrance or susceptibility variant. In addition we identified a known variant previously associated with arrhythmogenic right ventricular dysplasia type2 (ARVD2). Combining sets of prediction scores and reference databases appeared fundamental to predict the pathogenic potential of novel and rare missense variants in populations where genotype data are rare.
...
PMID:RYR2 sequencing reveals novel missense mutations in a Kazakh idiopathic ventricular tachycardia study cohort. 2497 18

To initiate the contraction of cardiomyocytes, Ca²⁺ is released from the SR to the cytosol via ryanodine receptors (RyRs), which are activated by the Ca²⁺-induced Ca²⁺ release mechanism (CICR). The activity of RyRs is regulated by both, cytosolic and SR luminal Ca²⁺. Deregulation of the CICR, by dysfunctional SR Ca²⁺ release or uptake, is frequently associated with cardiac pathologies (e.g. arrhythmias, CPVT, heart failure). Recently, the interest to directly measure changes of the free Ca²⁺ concentration within the SR ([Ca²⁺]_SR) has led to the application of low affinity Ca²⁺ indicators (mag-fluo-4, Fluo-5N) to follow changes of [Ca²⁺]_SR in cardiomyocytes from some species. However, direct measurement of Ca²⁺ signals from the SR have not been possible in freshly isolated mouse cardiomyocytes. Here, we show a new protocol optimized to measure changes of [Ca²⁺]_SR in mouse cardiomyocytes using fluorescent Ca²⁺ indicators and confocal microscopy. The application of this protocol permits the design of experimental studies with direct evaluation of SR Ca²⁺ in real time in various mouse models of cardiac disease, including transgenic animals harboring mutants of RyRs or other Ca²⁺ signaling proteins. The technique, in combination with these models, will help to understand how these diseases and mutations affect Ca²⁺ signals within the SR and the Ca²⁺ sensitivity of the RyRs for cytosolic and SR luminal Ca²⁺, thereby contributing to arrhythmias or weak heart beat.
...
PMID:Real-time intra-store confocal Ca²⁺ imaging in isolated mouse cardiomyocytes. 2743 64

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease characterized by a structurally normal heart and high lethality beginning in early childhood. The identification of its genetic bases made possible the discovery that arrhythmias are caused by intracellular calcium dysregulation. In the 9 years since the description of the genetic substrate of the disease, we have witnessed remarkable progress in the unraveling of the molecular mechanisms underlying its arrhythmogenesis. The impact of these discoveries extends beyond the field of inherited arrhythmias and sheds new light on the arrhythmogenic mechanisms in some more prevalent diseases characterized by abnormal calcium regulation, such as heart failure. Additionally, basic research studies led to the exploration of new therapeutic strategies with potential clinical impact in the near future in reducing the still high incidence of sudden death associated with these conditions. In the current review, the authors discuss the clinical and genetic features of CPVT, highlighting pathophysiologic insights derived from experimental research and future therapeutic targets.
...
PMID:Catecholaminergic Polymorphic Ventricular Tachycardia. 2877 Jul 16