Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two cases of malignant hyperthermia (MH) are presented. The first patient presented initially with tachyarrhythmia intraoperatively and rapid onset of MH crisis. Nasopharyngeal temperature of 43 degrees C was attained after 15-20 minutes of anaesthesia. The patient eventually died of myocardial failure despite external cardiac massage, inotropic support and ventricular pacing. The second patient presented with increasing endogenous hypercarbia following the administration of suxamethonium and isoflurane. The use of the end tidal carbon dioxide monitor led to an early diagnosis of MH. The early use of dantrolene may have contributed to the favourable outcome.
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PMID:Malignant hyperthermia. 239 48

Myotonia is defined as a persistent contraction of skeletal muscles after their stimulation. This contracture is not prevented or relieved by regional anaesthesia or muscle relaxants. The sensitivity to non-depolarizing muscle relaxants is usually normal. Suxamethonium, neostigmine, hypothermia, a rise in kalaemia should be avoided. There have been case reports of malignant hyperthermia in patients with myotonia congenita. Dystrophia myotonica is the second most frequent of the inherited muscle diseases, after Duchenne's dystrophy. The severity of the disease is due more to the muscular atrophy and the multiple organ involvement than to the abnormal contraction. Atrioventricular heart block and dysrhythmias are more common than heart failure. Prolonged apnoea and pneumonia are the main risks of anaesthesia. In severe cases, exists a restrictive respiratory insufficiency which is preceded by a fall in the maximum expiratory pressure. Dysphagias and inefficient coughing may occur early. An increased susceptibility to hypnotic drugs and opiates is a common feature. Spontaneous sleep apnoeas should be sought before anaesthesia, especially by using pulse oximetry. The anaesthetic implications are reemphasized.
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PMID:[Anesthesia in myotonia]. 253 24

We present a 17-year-old boy with Becker muscular dystrophy (BMD) who developed hyperthermia and heart failure after general anesthesia. He presented clinical features of malignant hyperthermia (MH), and had masseter spasm and elevated body temperature (38.7 degrees C) with very high serum CK activity (107,000 IUl-1). Dystrophin tests confirmed a clinical diagnosis of BMD in the patient, i.e. faint and patchy immunostaining pattern of skeletal muscle, truncated dystrophin protein and a deletion of exons 3 and 4 of the dystrophin gene. To inquire into the mechanism of MH associated in the patient, we tested caffeine contracture reaction by the skinned fiber method. We found an increased sensitivity to caffeine only in type 1 muscle fibers. The rate of Ca(2+)-induced Ca2+ release (CICR) was normal, suggesting that the mechanism of "MH" observed in our patient with BMD is not the same as that of classical MH. A possible mechanism might be related to derangements of the sarcoplasmic reticulum membrane in BMD, which sensitize the membrane to caffeine or other agents.
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PMID:Malignant hyperthermia in a patient with Becker muscular dystrophy: dystrophin analysis and caffeine contracture study. 771 42

Calcium signalling in cells is dependent on a communication between channels/ transporters in two membrane structures: the cell membrane and the membranes of endo- and sarcoplasmic reticula (ER/SR). In general, cytosolic Ca2+ can be raised by influx of calcium over the cell membrane through three types of channels: voltage-, receptor-, and store-operated channels (VOCs, ROCs and SOCs). This small Ca2+ influx is most often amplified by a Ca2+ release from the ER/SR through two types of channels: the IP3-receptor and the ryanodine receptor (RyR), which are huge proteins identified and cloned in recent years. We focus on the 'synaptic' connection between VOCs (L-type calcium channels) and RyRs of the SR in heart and skeletal muscle. Depolarization of the cell membrane (an action potential) opens the VOC and moves it in the membrane. One VOC triggers opening of a certain number of underlying RyRs that together release a quantum of calcium from the SR, a calcium spark. The communication between the VOC and RyRs is probably achieved primarily by a mechanical link in skeletal muscle (voltage-controlled calcium release), and by the small inward calcium flux through the VOC in the heart (calcium-induced calcium release, CICR). Conditions as different as heart failure, myasthenia gravis, malignant hyperthermia, and skeletal muscle fatigue, may be examples of deteriorated control or function of the RyR.
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PMID:Intracellular calcium signalling in striated muscle cells. 939 86

A whole range of cell functions are regulated by the free cytosolic Ca(2+)concentration. Activator Ca(2+)from the extracellular space enters the cell through various types of Ca(2+)channels and sometimes the Na(+)/Ca(2+)-exchanger, and is actively extruded from the cell by Ca(2+)pumps and Na(+)/Ca(2+)-exchangers. Activator Ca(2+)can also be released from internal Ca(2+)stores through inositol trisphosphate or ryanodine receptors and is taken up into these organelles by means of Ca(2+)pumps. The resulting Ca(2+)signal is highly organized in space, frequency and amplitude because the localization and the integrated free cytosolic Ca(2+)concentration over time contain specific information. Mutations or functional abnormalities in the various Ca(2+)transporters, which in vitro seem to induce trivial functional alterations, therefore, often lead to a plethora of diseases. Skeletal-muscle pathology can be caused by mutations in ryanodine receptors (malignant hyperthermia, porcine stress syndrome, central-core disease), dihydropyridine receptors (familial hypokalemic periodic paralysis, malignant hyperthermia, muscular dysgenesis) or Ca(2+)pumps (Brody disease). Ca(2+)-pump mutations in cutaneous epidermal keratinocytes and cochlear hair cells lead to, skin diseases (Darier and Hailey-Hailey) and hearing/vestibular problems respectively. Mutated Ca(2+)channels in the photoreceptor plasma membrane cause vision problems. Hemiplegic migraine, spinocerebellar ataxia type-6, one form of episodic ataxia and some forms of epilepsy can be due to mutations in plasma-membrane Ca(2+)channels, while antibodies against these channels play a pathogenic role in all patients with the Lambert-Eaton myasthenic syndrome and may be of significance in sporadic amyotrophic lateral sclerosis. Brain inositol trisphosphate receptors have been hypothesized to contribute to the pathology in opisthotonos mice, manic-depressive illness and perhaps Alzheimer's disease. Various abnormalities in Ca(2+)-handling proteins have been described in heart during aging, hypertrophy, heart failure and during treatment with immunosuppressive drugs and in diabetes mellitus. In some instances, disease-causing mutations or abnormalities provide us with new insights into the cell biology of the various Ca(2+)transporters.
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PMID:Abnormal intracellular ca(2+)homeostasis and disease. 1094

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.
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PMID:Involvement of the cardiac ryanodine receptor/calcium release channel in catecholaminergic polymorphic ventricular tachycardia. 1180 5

Ryanodine receptors (RyRs) are the major sarcoplasmic reticulum calcium-release channels required for excitation-contraction coupling in skeletal and cardiac muscle. Mutations in RyRs have been linked to several human diseases. Mutations in the cardiac isoform of RyR2 are associated with catecholaminergic polymorphic ventricular arrhythmias (CPVT), and arrhythmogenic right ventricular dysplasia type 2 (ARVD2), whereas mutations in the skeletal muscle isoform (RyR1) are linked to malignant hyperthermia (MH) and central core disease (CCD). RyRs are modulated by several other proteins, including the FK506 binding proteins (FKBPs), FKBP12 and FKBP12.6. These immunophilins appear to stabilize a closed state of the channel and are important for cooperative interactions among the subunits of RyRs. This review discusses the regulation of RyRs by FKBPs and the possibility that defective modulation of RyR2 by FKBP12.6 could play a role in heart failure, CPVT, and ARVD2. Also discussed are the consequences of FKBP12 depletion to skeletal muscle and the possibility of FKBP12 involvement in certain forms of MH or CCD.
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PMID:Regulation of ryanodine receptors by FK506 binding proteins. 1545 14

Identification of the genetic basis of human diseases linked to dysfunctional free calcium (Ca2+) signaling has triggered an explosion of interest in the functional characterization of the molecular components regulating intracellular Ca2+ homeostasis. There is a growing appreciation of the central role of intracellular ryanodine-sensitive Ca2+ release channel (RyR) regulation in skeletal and cardiac muscle pathologies, including malignant hyperthermia, heart failure, and sudden cardiac death. The use of cloned RyR isoforms and recombinant expression techniques has greatly facilitated the elucidation of the molecular basis of RyR Ca2+ release functionality. This review will focus on the recombinant techniques used in the functional characterization of recombinant RyR isoforms and the insights that these approaches have yielded in unraveling the mechanistic basis of RyR channel functionality.
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PMID:Toward a molecular understanding of the structure-function of ryanodine receptor Ca2+ release channels: perspectives from recombinant expression systems. 1585 32

Ryanodine receptors (RyRs) are high conductance intracellular cation channels that release calcium ions from stores such as the endoplasmic reticulum and sarcoplasmic reticulum. Although RyRs are expressed in many cell types, their roles have only been extensively characterised in tissues in which they are abundant: RyR1 is essential for excitation-contraction coupling in skeletal muscle; whereas RyR2 is required for the analogous signal transduction pathway in heart. Defects in RyR1 cause malignant hyperthermia and a spectrum of myopathies in skeletal muscle; whereas RyR2 dysregulation can result in fatal cardiac arrhythmias and is involved in heart failure. Altered RyR gating has been implicated in a range of other diseases, including epilepsy, neurodegeneration, pain and cancer. RyRs interact with a range of toxic substances, providing insights into their functional and structural properties. Consequently, these channel complexes represent potential therapeutic targets for treatment of numerous diseases. Furthermore, strategies for combating multicellular parasites and agricultural pests could exploit pharmacological differences between their RyRs and those of vertebrates. However, available pharmacological tools for manipulation of RyR gating are generally unsuitable for clinical, veterinary or agricultural use, owing to their lack of selectivity, inappropriate solubility in the aqueous or lipid environment, or generation of side-effects. The expression, subcellular distribution and gating of RyRs is modified by a wide variety of cellular proteins, some of which are expressed in a developmentally or tissue-restricted manner. This commentary examines the possibility of manipulating the expression and function of such proteins in order develop new drugs acting on RyR channel complexes.
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PMID:Ryanodine receptor calcium channels and their partners as drug targets. 2009 79

Ryanodine receptors (RyR) regulate intracellular Ca(2+) release in many cell types and have been implicated in a number of inherited human diseases. Over the past 15 years genetically engineered mouse models have been developed to elucidate the role that RyRs play in physiology and pathophysiology. To date these models have implicated RyRs in fundamental biological processes including excitation-contraction coupling and long term plasticity as well as diseases including malignant hyperthermia, cardiac arrhythmias, heart failure, and seizures. In this review we summarize the RyR mouse models and how they have enhanced our understanding of the RyR channels and their roles in cellular physiology and disease.
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PMID:Ryanodine receptor studies using genetically engineered mice. 2021 99


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